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Meds, Mind, Body & Benefits => Research News & Studies => Topic started by: J220 on June 30, 2008, 01:30:58 pm

Title: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: J220 on June 30, 2008, 01:30:58 pm
From http://www.sciencedaily.com/releases/2008/06/080630093611.htm :

ScienceDaily (June 30, 2008) — Researchers at the University of Pennsylvania School of Medicine and collaborators are using minute, naturally occurring proteins called zinc fingers to engineer T cells to one day treat AIDS in humans.

"By inducing mutations in the CCR5 gene using zinc finger proteins, we've reduced the expression of CCR5 surface proteins on T cells, which is necessary for the AIDS virus to enter these immune system cells," explains first author Elena Perez, MD, PhD, Assistant Professor of Pediatrics at Penn. "This approach stops the AIDS virus from entering the T cells because it now has an introduced error into the CCR5 gene."

Some people are born with a mutation on their CCR5 gene and therefore do not have a working CCR5 receptor on the surface of their T cells. These rare individuals are immune to HIV infection and seemingly are not affected by the non-functional CCR5 protein. The zinc finger approach aims to mimic this natural immunity.

Perez performed the research while a postdoctoral fellow in the lab of senior author Carl June, MD, Director of Translational Medicine at the Abramson Family Cancer Research Institute, and a Professor of Pathology and Laboratory Medicine at Penn. Perez is also an attending physician with the Children's Hospital of Philadelphia in the Division of Allergy and Immunology.

Normally, zinc fingers bind to different bases in the DNA sequence to regulate the activity of genes. The zinc fingers used in this experiment were designed to bind to specific DNA sequences in the CCR5 gene. The CCR5 protein is one of the two cell-surface receptors needed for HIV to gain entry into a T cell in order to replicate.

In this study, the zinc finger protein brings a DNA enzyme to the CCR5 gene to cut a portion of its sequence, but due to the repair process a new mutation arises in the CCR5 protein, rendering it non-functional. Without a functional CCR5 protein on the cell's surface, HIV cannot enter, presumably leading to resistance to HIV infection.

The researchers demonstrated this process in cell culture and in a mouse model. For the animal part of the study, the investigators used healthy human CD4 T cells and added DNA that expresses the zinc fingers, which modifies the CCR5 co-receptor. They grew the engineered cells in tissue culture flasks and transferred them into immune-deficient mice infected with HIV. "We followed them over time and showed that those mice that received the zinc-finger-treated cells showed less viral load than controls and improved CD4 counts," says Perez.

The researchers are planning a clinical trial in humans in which T cells from HIV patients would have their CCR5 gene deliberately knocked out. These modified T cells could then be infused back into the patients to re-establish their immune system and decrease their viral load.

Dr. Perez and Dr. June have no financial relationship with Sangamo.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: NYCguy on July 01, 2008, 06:50:03 pm
Sangamo previously claimed that there would be a trial in 2007.  Let's hope they start one soon, rather than sending out more press releases.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: bimazek on July 02, 2008, 05:24:09 pm
http://www.sciencenews.org/view/generic/id/33799/title/HIV_knockout

a little more science detail on this discovery if you are into that

my hope is that in 5 years we will all have some non toxic treatment

haart may still be arround in some cases like mutated virus that is resistant

maybe 7 years is my hope
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: bimazek on July 04, 2008, 01:52:35 pm
this looks like it could be a major major breakthrough - lets hope that there rapid movement forward - lot of detailed science here

Find a specific gene and then  turn it on or off.
ZFP-Therapeutics are designed to activate or repress specific genes relevant to human diseases. More...
http://www.sangamo.com/index.php

TEN DIAGRAMS TO EXPLAIN HOW IT WORKS
http://www.sangamo.com/tech/our_tech_ex.html
 Engineering Transcription Factors to Regulate Genes
Transcription factors are naturally occurring proteins that function within the nucleus of a cell to regulate gene expression. Transcription factors function by binding to specific sites on DNA and causing nearby genes to be turned on or off. (fig. A)

PDF on how they have had success with AIDS
http://files.shareholder.com/downloads/SGMO/351574819x0x209704/40e1ddfe-7186-4503-8904-8751b5b3fe55/SGMO_News_2008_6_30_General_Releases.pdf

www.sangamo.com  is the company that invented all this!!


details on technology of ZPT
http://www.sangamo.com/tech/tech.html
how USLCA is using sagamo ZPT tech to treat aids
http://www.sangamo.com/human/human_thera_overview.html#HIV



Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS)
HIV infection results in the death of immune system cells and thus leads to AIDS, a condition in which the body’s immune system is depleted to such a degree that the patient is unable to fight off common infections and ultimately  succumbs to opportunistic infections or cancers.  CCR5 is the co-receptor for HIV entry into T-cells and without CCR5 expressed on their surface, HIV cannot infect these cells.  A population of individuals has been identified that is immune to HIV infection, despite multiple exposures to the virus. They have a natural mutation, CCR?532, that results in the expression of a shortened, non-functional CCR5 protein. This mutation appears to have no observable deleterious effect on the growth or survival or these individuals. We are using our ZFN-mediated gene disruption technology to disrupt the CCR5 gene in cells of a patient’s immune system to make these cells permanently resistant to HIV infection.  The aim is to provide a population of HIV-resistant cells that can fight opportunistic infections. In collaboration with scientists at the University of Pennsylvania and the University of Los Angeles California, UCLA, we are pursuing both ex- and in vivo approaches in T-cells and hematopoietic. Sangamo anticipates filing an IND for this therapeutic in 2008.

cute guys who helped invent this technology
http://www.sangamo.com/discovery/discovery.html


http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1410.html
Article abstract
Nature Biotechnology
Published online: 29 June 2008 | doi:10.1038/nbt1410
Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases
Abstract
Homozygosity for the naturally occurring Delta32 deletion in the HIV co-receptor CCR5 confers resistance to HIV-1 infection. We generated an HIV-resistant genotype de novo using engineered zinc-finger nucleases (ZFNs) to disrupt endogenous CCR5. Transient expression of CCR5 ZFNs permanently and specifically disrupted approx50% of CCR5 alleles in a pool of primary human CD4+ T cells. Genetic disruption of CCR5 provided robust, stable and heritable protection against HIV-1 infection in vitro and in vivo in a NOG model of HIV infection. HIV-1-infected mice engrafted with ZFN-modified CD4+ T cells had lower viral loads and higher CD4+ T-cell counts than mice engrafted with wild-type CD4+ T cells, consistent with the potential to reconstitute immune function in individuals with HIV/AIDS by maintenance of an HIV-resistant CD4+ T-cell population. Thus adoptive transfer of ex vivo expanded CCR5 ZFN–modified autologous CD4+ T cells in HIV patients is an attractive approach for the treatment of HIV-1 infection.


http://investor.sangamo.com/stockquote.cfm?benchmark1=&Event1=&DisplayType=Area&Period=560&CustomFromDate=6%2F20%2F2004&CustomToDate=10%2F30%2F2004
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: John2038 on January 31, 2009, 06:03:39 pm
Milestone Achieved A Year Ahead of Schedule (Jan 12, 2009)

Sangamo BioSciences, Inc. (Nasdaq: SGMO) today announced it has reached a major production capacity milestone as part of its agreement with Sigma-Aldrich Corporation (Nasdaq: SIAL) to commercialize zinc finger nuclease reagents (ZFNs) for research applications. The milestone triggers a payment of $1.0 million to Sangamo.

Full story (http://investor.sangamo.com/releasedetail.cfm?ReleaseID=358637)

More about ZFN and Video (http://www.compozrzfn.com/)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on June 05, 2009, 03:34:37 pm

The researchers are planning a clinical trial in humans in which T cells from HIV patients would have their CCR5 gene deliberately knocked out. These modified T cells could then be infused back into the patients to re-establish their immune system and decrease their viral load.


Update, this article says they are starting to test this on humans already:

Trial Begins for HIV Gene Therapy
By Aaron Rowe   February 3, 2009  |  4:00 am  |  Categories: Biotech, Medicine & Medical Procedures

Gene therapy that could immunize people against the most common type of HIV is ready to be tested on humans.

Recruiting for the trial began Tuesday, and the first people to receive the experimental treatment will be HIV patients with drug-resistance problems.

"We do have good treatments for HIV. That has been one of the most successful stories of the last 20 years in medicine," said Pablo Tebas, an infectious disease expert at the University of Pennsylvania.

"However, over time, if the medications are not taken properly, individuals develop resistance to the HIV treatments, so they tend to have more limited therapeutic options."

Since the discovery that a small portion of people who are exposed to HIV do not get infected, scientists have been working to discover the secret to those people’s resistance and how to make others resistant as well.

It turns out that most people have a gene called CCR5, which makes them vulnerable to HIV infections. The naturally resistant people have mutant CCR5 genes that inhibit HIV.

Previously, scientists found that by cutting the CCR5 gene out of white blood cells involved in the immune response known as T-cells, they could protect a tube full of human cells from the virus. The gene editing technique relies on proteins called zinc finger nucleases that can delete any gene from a living cell.

In theory, zinc finger nucleases could give that immunity to anyone.

The procedure is simple: Take some healthy T-cells out of an HIV patient, clip out their CCR5 genes, grow more of these clipped T-cells in a dish, and then put them back in the patient.

"In this first study we will re-infuse approximately 10 billion of these cells back into the participants, and we will see if it is safe and if those cells inhibit HIV replication in vivo," said Tebas. "We know they do in the test tube."

LINK:

http://www.wired.com/wiredscience/2009/02/hivtreatment/

CLINICAL TRIAL LINK:

http://clinicaltrials.gov/ct2/show/NCT00842634
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on June 06, 2009, 03:33:34 pm
Can you feel the love?

[attachment deleted by admin]
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dadx4 on June 29, 2009, 10:23:29 am
Are any of you in this trial?  How's it going if you are participating, I know they are still recruiting.  They are only taking 12 patients to start though. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: brazilianman on July 06, 2009, 08:35:11 pm
hello, I'm from Brazil and I like the forum on anti-ps is a good theory. I would like to know what the strength of the forum to ask for drug companies on research? much is spoken but not proven. vrx496? pro 140? Anybody know about this? sorry bad English.


Antibody specificities associated with neutralization breadth in plasma from HIV-1 subtype C infected blood donors
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: brazilianman on August 23, 2009, 05:43:57 pm
 ???  any news? Zinc finger where? the study is stopped or moving?   ???
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on August 23, 2009, 06:35:58 pm
???  any news? Zinc finger where? the study is stopped or moving?   ???

The trial started February 2009, it's too soon to know anything.

Estimated Study Completion Date:   March 2011
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: brazilianman on August 24, 2009, 08:41:18 am
Inch.

seems not yet begun. they are recruiting candidates. this treatment model can work.

this method is not like the dr. hutter?
somebody registered?

I'm optimistic. ;D

http://clinicaltrials.gov/ct2/show/NCT00842634
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dadx4 on August 24, 2009, 09:57:50 pm
I think they have all of the candidates now and they may have an update December of next year.   Could you imagine if this actually works...
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Carlos3000 on September 08, 2009, 05:52:05 pm
news about Zinc Fnger


http://www.reuters.com/article/pressRelease/idUS116019+08-Sep-2009+PRN20090908
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: xman on September 16, 2009, 05:13:14 pm
i'm a bit concerned about the safety of this approach. even if we know that persons lack this gene naturally we still don't know if they have another protein or enzyme which replaces its function. if you simply turn off the ccr5 coreceptor we don't know if this could interact negatively in the normal immune function. i guess this is a reason why the first clinical phases are so long.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: marius68 on September 23, 2009, 08:13:12 am
Zinc Finger therapy is progressing!! Most likely it means results from current trial are good!!

http://investor.sangamo.com/releasedetail.cfm?ReleaseID=410950


Sangamo BioSciences Announces Plans to Initiate a Second Clinical Trial of CCR5-ZFP Therapeutic to Treat HIV/AIDS

Expansion of Program Will Test Repeat Dosing Protocol of SB-728-T

RICHMOND, Calif., Sept 23, 2009 /PRNewswire-FirstCall via COMTEX News Network/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that the US Food and Drug Administration (FDA) has reviewed and accepted an Investigational New Drug (IND) application to initiate an open-label, repeat-dosing Phase 1 clinical trial (SB-728-T-902) of the company's ZFN-based therapeutic, SB-728-T. A single dose Phase 1 clinical study of SB-728-T was initiated in February 2009 and is ongoing at the University of Pennsylvania. Both Phase 1 studies are designed primarily to evaluate the safety and tolerability of this ZFP Therapeutic(TM) approach, however subjects' CD4 T-cell counts, levels of CCR5-modified T-cells and viral burden will also be monitored.

"Opening a second Phase 1 clinical trial of this exciting new approach to HIV/AIDS treatment enables us to expedite clinical and commercial development of SB-728-T. We are very pleased with the FDA's decision enabling us to expand this program and move forward quickly with a repeat-dosing trial," said Dale Ando, M.D., Sangamo's chief medical officer and vice president of therapeutic development.

"The best approach to controlling HIV is by preventing infection of cells in the first place. Since 1996, when CCR5 was validated as a target for HIV therapy, the goal has been to recapitulate the naturally-occurring protection against viral infection exhibited by individuals who have the CCR5-delta32 mutation. We have the ability to disrupt the CCR5 gene and make human T-cells resistant to infection by CCR5-specific strains of HIV. In this trial we will be evaluating SB-728-T in subjects that have well-controlled levels of virus but have sub-optimal recovery of CD-4+ T-cell counts despite long-term triple drug therapy. This group represents approximately thirty percent of all HIV-infected patients in the US and may particularly benefit from this novel T-cell ZFP Therapeutic approach."

Based on Sangamo's zinc finger DNA-binding protein nuclease (ZFN) technology, SB-728-T has been shown in an animal model of HIV infection to lead to an increase in CD4+ T-cell counts, a reduction in viral load and expansion of CCR5-modified T-cells, suggesting resistance to HIV.

"Although it is still early days, we are encouraged by what we have seen in pre-clinical experiments and in the ongoing Phase 1 clinical trial that is being run by collaborators at the University of Pennsylvania," commented Edward Lanphier, Sangamo's president and CEO. "This new study is another important step in our mission to establish ZFP Therapeutics as a major new therapeutic product development platform. Moving our first ZFN technology-based product efficiently through the development process is vital to that goal. SB-728-T represents a new treatment paradigm for the treatment of HIV and we are very excited to expand its clinical development."

CCR5 is a co-receptor that enables HIV to enter and infect cells of the immune system. It has been observed that individuals carrying a natural mutation of their CCR5 gene, CCR5-delta32, are highly resistant to infection by HIV, despite high-risk behaviors. These individuals, lacking a functional CCR5 (approximately 1-2% of the general population), are otherwise immunologically "normal". A variety of small molecule and antibody antagonists of CCR5 binding have been tested and developed as potential therapeutic agents for the treatment of HIV infection. In addition, there is a recent report of a patient who had both HIV infection and leukemia and received a bone marrow transplant from a donor carrying the CCR5 mutation. After the successful bone marrow transplant, HIV treatment was discontinued and the virus could not be found in the circulating blood several months after the procedure. Sangamo's ZFNs are designed to modify the DNA sequence encoding CCR5. This modification can occur directly in T-cells with only a brief exposure to the ZFNs. Once the modification is made to the T-cell's CCR5 gene it is permanently disrupted.

About the SB-728-T Clinical Trial (SB-728-T-902)

The study is an open-label Phase 1 clinical trial to evaluate the safety and tolerability of repeat infusions of autologous (a patient's own) CD4+ T cells genetically modified at the CCR5 gene by CCR5-specific ZFNs (SB-728-T). The trial will enroll a total of nine HIV infected subjects on long-term, stable anti-retroviral therapy whose virus is undetectable in their blood by conventional methods but who have exhibited suboptimal CD4+ T-cell gains. The trial will have three dosing cohorts. The first cohort to be treated will receive a single dose, the second cohort, two doses at fourteen day intervals and the third cohort, three doses at fourteen day intervals. The subjects in each cohort will be treated sequentially and monitored for 2 months after their last treatment before an additional subject is treated. After this period of evaluation and monitoring has passed successfully, the next cohort will be treated, again sequentially. Subjects will remain on their existing antiviral therapy while receiving treatment with SB-728-T. The primary objective of the study is to evaluate the safety and tolerability of SB-728-T. In addition to safety monitoring, data will be collected on the expansion and persistence of ZFN-modified cells, CD4+ cell counts and viral load.

Preclinical Data

Preclinical data on SB-728-T were published in the journal Nature Biotechnology (Perez E. E. et al., Nat Biotechnol. 2008 Jul; 26(7):808-16.) and presented at the joint meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the Infectious Diseases Society of America (IDSA) in Washington, DC in October 2008. The results demonstrate that a one-time exposure to CCR5-specific ZFNs resulted in the generation of an HIV-resistant population of human primary T-cells by the permanent genetic modification of the CCR5 gene. These ZFN-modified CD4 T-cells expanded stably in HIV-infected cultures for several weeks and behaved identically to untreated T-cells except that they were resistant to infection by HIV. ZFN treated primary CD4 T-cells and transformed CD4 cell lines resisted infection with R5-tropic HIV (virus that uses the CCR5 co-receptor to enter cells), resulting in enrichment of ZFN-generated CCR5-disrupted cells in the population upon long-term exposure to virus (>50 days). Importantly, in the presence of HIV, ZFN-modified CD4 T-cells also preferentially expanded in a mouse model. The modified cells were infused into mice that lack a normal immune system and thus do not reject human cells. After 33 days, the mice were sacrificed and analyzed for the presence of ZFN-modified cells. Researchers determined that ZFN-modified cells engrafted normally in the mouse and that the proportion of modified cells present at the end of the experiment was greater than two to three fold higher in mice in the presence of HIV infection (p=0.008). In additional experiments, it was determined that 50 days after infection, mice given the ZFN-modified cells had increased numbers of CD4 cells and a statistically significant reduction in viral load in their peripheral blood (P<0.001) compared to mice given control cells. These data suggest that, in the presence of HIV, the ZFN-modified cells have a selective advantage allowing them to evade infection and destruction.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on September 23, 2009, 11:08:36 am
I have lots of faith in zinc finger and other technologies that knock out CCR5 but I was reading the article on thebody.com with Dr. Jeffrey Laurence, updating the status of the patient in Berlin who was cured of both HIV and Leukemia (talk about hitting the jackpot) and he said existing technologies are not able to knock out CCR5 100% which is what is needed. I actually thought zinc finger was able to knock it out 100% in the cells extracted from a particular patient so this is surprising. This is what he said about current technologies for mutating CCR5 (what he describes in the second paragraph is what I thought ZFN does, at least that's how it's been described in the literature from Sangamo):

The ideas are out there on how to do it. Basically, what you need to do is mutate this gene in every single cell that you're going to transplant into a person. What if we just took the person's own cells, or that of the next available donor that walks in the door who happens not to have the CCR5 mutation -- as statistically they won't -- and genetically give them the mutation?

Can we knock out the gene for CCR5? That's called genetic engineering. We're really good at doing genetic engineering in one cell. But the average person getting transplanted is getting a few billion cells, and we have to guarantee that 100.0 percent of those few billion cells all have their genes modified. We could take a few hundred or a few thousand cells, make certain that every single one of them has that gene modified, and then grow them into billions of cells that we can inject back into the patient, but we don't know how to do that.

Some of the physician scientists that I mentioned that I invited to our think tank in September are working on that. They're working on it in mice, and they're working on it in monkeys. With current technology, in a monkey or in a mouse or in a test tube, you can knock out the CCR5 gene in maybe as much as 90 percent of the cells. But we need 100.0 percent of cells to be CCR5 negative, because if even one little cell has the capacity to be infected with HIV and it starts multiplying in your body, that's the end of your cure.

So I think it's partly a technology problem, and that's where research comes in. We know what we need to knock out: CCR5. We have people looking, as I mentioned earlier, for other things that might account for other people being resistant to getting infected with HIV. If we find those changes, we'll have other targets to knock out.

All we need to do now is come up with better technologies than the small interfering RNAs, the zinc finger nucleases, the oligonucleotide reductases, the ribozymes and so forth. All these words for ways that we knock stuff out to get us closer to 100 percent. That's where research is so important.

"This is an important area of research that needs multiple people looking at it from multiple different angles because none of those technologies are 100 percent accurate in knocking a single gene out in 100 percent of the cells."

I have a lot of faith in this kind of research. It's going to enable us to just take cells from the first acceptable donor, as if the patient didn't have HIV, knock out that gene and give it to the patient, and replicate what happened in Berlin.

LINK:

http://www.thebody.com/content/art53624.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: brazilianman on September 23, 2009, 06:50:55 pm
Inch
I see zinc finger with other therapies. If the project goes well Adaptimmune can join them.
One is a hunt for hiv other protects the cell and the hiv

;D

Bman
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on September 23, 2009, 08:22:08 pm
Even if you can't modify 100% of t-cells with the CCR5 mutation, it seems that this approach would have a lot of therapeutic value.  Afterall long-term non-progressors still have varying levels of HIV since they are not able to eradicate it.  And if HIV continues to kill off the non-mutated t-cells, while the modified ones are repopulating the CD4s, won't they eventually comprise most if not all of the t-cells in a treated individual?  Maybe I'm not understanding how this works, but if this therapy can offer the possibility of many years off meds, I'd welcome it as a major breakthrough. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on September 24, 2009, 01:23:20 am
brazilianman & cosmicdancer, you both make very good points.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: hahaha on September 24, 2009, 02:15:48 am
How come nobody mentioned about CXCR4 issue in zing finger treatment? Does it matter still?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on September 24, 2009, 11:26:31 am
How come nobody mentioned about CXCR4 issue in zing finger treatment? Does it matter still?

There are other therapies looking at blocking entry through CXCR4 but as far as I am aware, zinc finger does not work with CXCR4.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on September 24, 2009, 01:45:29 pm
How come nobody mentioned about CXCR4 issue in zing finger treatment? Does it matter still?

Sangamo (the Zinc Finger people) have a CXCR4 project in preclinical.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on September 24, 2009, 02:42:41 pm
Sangamo (the Zinc Finger people) have a CXCR4 project in preclinical.

I know there are CXCR4 projects but I didn't know there were any from Sangamo using ZFN, that's awesome. I'll go Google it now ;)

EDITED TO ADD: Freewillie, I found an entry inhibitor called AMD-8445, which I guess is it but I couldn't find much. Do you have any more info on it?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on September 24, 2009, 03:05:26 pm
EDITED TO ADD: Freewillie, I found an entry inhibitor called AMD-8445, which I guess is it but I couldn't find much. Do you have any more info on it?

Here's a link to a slide from a recent Sangamo presentation which mentions it.  Note that it's the last entry at the bottom.  

http://cc.talkpoint.com/ubsx001/092109a_ke/content/116_C8PIWBN/slides/Slide14.png

Their CXCR4 project was also mentioned earlier this week in an investor conference call.

Rock on with Zinc Finger!!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: marius68 on September 28, 2009, 07:46:07 pm
Sangamo will be updating their ZF program on October, 5. They seem to be very active lately!!! Can't wait for the end of the clinical trials!!

Sangamo BioSciences Announces Presentation at the JMP Securities Healthcare Conference

RICHMOND, Calif., Sept 28, 2009 /PRNewswire-FirstCall via COMTEX News Network/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that Edward Lanphier, Sangamo's president and CEO, will provide an update on the progress of Sangamo's ZFP Therapeutic(TM) development programs and an overview of the company's business strategy at 9:30 am ET on Monday, October 5, 2009 at the Fourth Annual JMP Securities Healthcare Focus Conference which will be held in New York City.

The presentation will be webcast live and may be accessed via a link on the Sangamo BioSciences website in the Investor Relations section http://investor.sangamo.com/index.cfm under Events and Presentations. The presentation will be archived on the Sangamo website for two weeks after the event.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: marius68 on September 28, 2009, 10:00:08 pm

An interesting study was recently published on the outcome of gene therapy. From the abstract: "The modelling indicates a single infusion of HSC cell-delivered gene therapy can impact on HIV viral load and CD4 T-lymphocyte count. Given that gene therapy avoids the complications associated with HAART, there is significant potential for this approach in the treatment of HIV."

http://www.ncbi.nlm.nih.gov/pubmed/19777528?ordinalpos=38&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum


Through mathematical modeling anti-HIV gene therapy was analyzed. in particular the OZ1 ribozyme of Dr. Mitsuyasu. This was  discussed before (link following) but I decided to include under the ZFT topic since there seems to be a lot of activity from sangamo.

http://forums.poz.com/index.php?topic=25779.0

http://www.ncbi.nlm.nih.gov/pubmed/19219022?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on October 28, 2009, 05:45:14 pm
Sangamo just got a big grant to continue exploring ZFN. This particular grant is for silencing CCR5 in patients with AIDS-related lymphoma but the clinical trial that is currently ongoing from Sangamo (using ZFN) is for patients with HIV with no other complications.


Sangamo BioSciences Research Collaborators Awarded Grant From California Institute for Regenerative Medicine to Develop Zinc Finger Nuclease-Based Stem Cell Therapy for HIV/AIDS

$14.5 million award to bring ZFP HIV therapy to the clinic

RICHMOND, Calif, Oct 28, 2009 /PRNewswire-FirstCall via COMTEX News Network/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that the California Institute for Regenerative Medicine (CIRM) has granted a $14.5 million Disease Team Research Award to develop an AIDS-related lymphoma therapy based on the application of its zinc finger nuclease (ZFN) gene-editing technology in stem cells. The four year grant supports an innovative research project conducted by a multidisciplinary team of investigators led by John Zaia, M.D. the Aaron D. and Edith Miller Chair in Gene Therapy and chair of virology, City of Hope. The grant application entitled "Zinc Finger Nuclease-Based Stem Cell Therapy for AIDS" won the highest score of all grants CIRM received in this 1st round of Disease Team Research Award funding.

"Sangamo scientists have developed a ZFN-mediated gene-editing technology that has been demonstrated to make hematopoietic stem cells and mature immune system cells resistant to HIV infection," said Dr. Zaia. "This will be the first test of whether hematopoietic stem cells made HIV resistant using Sangamo's technology can correct the disease. If successful, our work could open the door to ZFN-based cell therapies for other important diseases."

Patients homozygous for a natural mutation (the delta-32 mutation) in the CCR5 gene are resistant to HIV infection by blocking the ability of the virus to enter a cell. Building on this observation, a study published in the New England Journal of Medicine in 2009 reported a potential "cure" in an AIDS patient with leukemia after receiving a bone marrow transplant from a "matched" donor with this delta-32 CCR5 mutation. This approach transferred the hematopoietic stem cells (HSC) residing in the bone marrow from the delta-32 donor, and provided a self-renewable and lifelong source of HIV-resistant immune cells. After transplantation, this patient was able to discontinue all anti-HIV drug treatments, CD4 counts increased, and the viral load dropped to an undetectable level, demonstrating effective transplantation of protection from HIV infection.

This CIRM Disease Team Research Award proposes an approach to modify a patient's own HSC to circumvent the need to find matched donors that carry the delta-32 CCR5 mutation and while providing a renewable and long-lasting source of HIV-resistant cells. Specifically, the grant funds the development of a ZFN approach to treat AIDS patients by first isolating their HSC, modifying them using CCR5-specific ZFNs, and then re-infusing them to reconstitute the immune system with CCR5-negative, HIV-resistant immune cells.

"We are delighted that this research proposal was chosen for funding by CIRM," commented Dr. Philip Gregory, Sangamo's chief scientific officer and vice president, research. "This grant brings together a team of world-renowned experts to develop this novel ZFN-based stem cell therapy for AIDS-related lymphoma through to the clinic. We look forward to working with the team which includes Paula Cannon, Ph.D., associate professor of Molecular Microbiology & Immunology, Keck School of Medicine of the University of Southern California, who has carried out extensive pre-clinical research using our technology in stem cells, and Dr. Zaia and his colleagues at City of Hope who are pioneers in hematopoietic cell transplantation."

"CIRM support for this program is a major validation of our ZFP Therapeutics platform both scientifically and financially and we are very pleased to be part of the exceptional team that received the highest score of all of the grants reviewed by CIRM," said Edward Lanphier, Sangamo's president and CEO.

The CIRM Disease Team Research Awards will fund actively managed multidisciplinary teams engaged in milestone-driven translational research for the development of stem cell-based therapies. The mission of these teams will be to conduct the necessary research and regulatory activities to prepare and file a complete, well supported Investigational New Drug Application (IND) with the Food and Drug Administration (FDA) (and, if desired, other regulatory agencies), to enable Phase I clinical testing.


LINK:

http://investor.sangamo.com/releasedetail.cfm?ReleaseID=419462
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on October 28, 2009, 08:14:46 pm
In addition to the grant for Sangamo, there will be $20 million for the AIDS Institute of the University of California, Los Angeles, which is partnering with Calimmune Inc. and using a different approach (RNAi) to silence CCR5.


Sangamo Gets Stem-Cell Grant for New AIDS Therapy
 
By Rob Waters

Oct. 28 (Bloomberg) -- Sangamo Biosciences, a developer of gene therapies based in Richmond, California, and the City of Hope, a nonprofit treatment center in Los Angeles, were awarded a $14.6 million grant to develop a new type of AIDS treatment.

California’s stem cell agency also will give $20 million to the AIDS Institute of the University of California, Los Angeles, which is partnering with Calimmune Inc., a closely held company based in Tucson, Arizona, to develop a related approach to AIDS treatment.

The grants are among a package of awards totaling more than $200 million approved today by the California Institute for Regenerative Medicine. The aim of the money is to help prepare treatments for human testing of stem-cell therapies within four years.

“It’s very exciting, a completely new paradigm for treating AIDS,” Jeff Sheehy, an HIV patient representative on the agency’s board, said about the City of Hope-Sangamo project in a telephone interview yesterday. “If it works, it could take AIDS treatment in a whole new direction.”

Sangamo fell 27 cents, or 4.4 percent, to $5.88 in composite trading on the Nasdaq Stock Market.

The two projects will use different methods to deactivate a gene called CCR5 that allows the AIDS virus to enter cells and spread infection, a new treatment approach. Both attempt to confer immunity to AIDS by mimicking the successful treatment of an AIDS patient in Germany.

Resisting Disease

That patient was able to stop drugs he had taken for 10 years, and remain healthy, after getting a transplant of stem cells from a donor with a rare gene variant known to resist the disease. The transplant also cured his leukemia, according to a report that appeared in February in the New England Journal of Medicine.

The unidentified 40-year-old patient had leukemia as well as HIV, the virus that causes AIDS, and needed a stem cell transplant to treat his cancer. The stem-cell donor was chosen because he is among the 1 percent of Caucasians who lack CCR5. Without the gene variant, the AIDS virus can’t enter a cell.

By giving the donor’s stem cells to the patient, doctors also gave him a new immune system that lacked CCR5. The experiment worked and the man is considered cured.

Kill the Cancer

The aim of the City of Hope-Sangamo effort is to treat patients with HIV and lymphoma, a blood cancer, killing the cancer by wiping out the patient’s immune system with chemotherapy. They will then use a genetic technology developed by Sangamo to modify the patients’ stem cells, which will be used to rebuild their immune system so they lack the CCR5 receptor.

“Cells that grow up following this process no longer have a functional copy of the CCR5 gene and no longer make the CCR5 protein,” said Philip Gregory, Sangamo’s chief scientific officer, in a telephone interview today. “If you don’t make it, then HIV can’t enter the cell. It’s a complete block to entry.”

The UCLA project will use a different method, attempting to turn off, or “silence,” the CCR5 gene using a technique known as RNA interference.

LINK:

http://www.bloomberg.com/apps/news?pid=20601124&sid=aP43cD4sNa8U

This is how these two projects were described in the New York Times:

Two projects will essentially try to replicate the reported cure last year of a patient with AIDS. The patient, in Berlin, also had leukemia and got a bone marrow transplant to treat that disease. But the bone marrow donor had a genetic makeup making him naturally resistant to H.I.V.

For a given patient with AIDS it would be nearly impossible to find a donor that is both a good match and naturally resistant to H.I.V. infection. But the two research teams plan to take a patient’s blood-forming stem cells and inactivate a gene to make them resistant to H.I.V., then put them back in the body.

LINK:

http://www.nytimes.com/2009/10/29/health/research/29stem.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on December 29, 2009, 10:30:47 pm
The New York Times has an article on ZFN and Sangamo:

In New Way to Edit DNA, Hope for Treating Disease

LINK:

http://www.nytimes.com/2009/12/29/health/research/29zinc.html?pagewanted=1&_r=1&ref=science
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: John2038 on January 19, 2010, 01:22:47 pm
Sangamo BioSciences Announces Presentation of Preliminary Data From Phase 1 Safety Trial of SB-728-T for HIV/AIDS
First Human Data from ZFN Clinical Program --ZFN-Modified Cells Well Tolerated and Able to Expand

RICHMOND, Calif., Jan 19, 2010

As expected, the subject's viral load increased during the STI. However, the kinetics of this subject's viral rebound was delayed. Presence of ZFN-modified cells in the GALT, an important HIV reservoir, demonstrates that we are achieving our pharmacologic biodistribution target. GALT HIV persistence in CD4+ T-cells is the reason that HIV is not eradicated in patients who are fully suppressed on highly active anti-retroviral treatment, or HAART. Ultimately, having a protected CD4+ T-cell population in the GALT may be extremely important in combating this disease.

"Our ZFN-based technology provides a totally new approach to HIV/AIDS with the aim of providing a reservoir of functional T-cells that are resistant to infection by HIV and available to fight opportunistic infections, and these data are an early indication that this may be possible."


Full Text (http://investor.sangamo.com/releasedetail.cfm?ReleaseID=438350)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: John2038 on January 20, 2010, 02:22:06 am
Just wanted to add a note:

1. The viral load increase during the STI was expected.
2. The viral rebound was delayed.
3. ZFN-modified T-cells were found also in the GALT, reaching the pharmacologic biodistribution target
4. ZFN-modified T-cells were well tolerated by the body and persisted in the circulation at stable levels for the duration of our monitoring.
5. In fact, more ZFN-modified T-cells were present at 20 weeks than were initially infused. Total CD4+ T-cell counts were also stable during this time.

These are important if not major achievements.

For those whose who haven't follows this research, here is how it work:

CD4+ T-cells are removed from the subject's blood and treated with Sangamo's ZFNs designed to modify the DNA sequence encoding the CCR5 gene.
This modification can occur directly in T-cells with only a brief exposure to the ZFNs. Once the CCR5 gene is modified, the gene is permanently disrupted in these cells.

The ZFN-modified T-cells are then infused into de patient.
These infused T-cell coexists with the original T-cells from the donor. So the expecred viral rebound but delayed.

As the infused T-cells can't be easily infected by HIV, they should at least remain present in the blood long enough for this approach to be interesting. And the results have shows so far (but in one patient) that not only it is the case, but that they persisted in the circulation at stable levels and even more, at 20 weeks (5 months) after the infusion.
In more the CD4 count have remain stable, which is what was also important.
The viral rebound was due to the infection of the original T-cell of this patient.

As such, we can dream that we can maintain with this appraoch a good level of healthy CD4, despite for eg viral failure. We can also hopes to boost the immune system of people undetectable.
Ultimately, we can hopes to better fight the residual viremia despite being UD, especially with a CD8 boost coming from another technology. As long as the CD4 level is in the normal range, despite a viral load detectable, the risk of developing OI/non-OI might be lowered (just a hope with no proof).
Finally, there are virtually no limits in the number of time the T-cell we can infused (excepting an economical limit), so such T-cell can help in the maintenance (and why not, the recovery) of exhausted immune systems.

All these are personal assumption, and only time will say. Lets hopes this can extends the life expectancy, delay the time to start HAART, allows STI, etc.. Dreaming a bit is not forbidden.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on February 23, 2010, 05:53:47 pm
Sangamo is starting a ZFN clinical trial in San Francisco.

LINK:

http://clinicaltrials.gov/ct2/show/NCT01044654?term=Sangamo&rank=1
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on February 25, 2010, 09:47:04 am
Another step in the right direction for the medicine of the (near?) future: Gene Therapy.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on March 03, 2010, 09:26:49 pm
RICHMOND, Calif., March 3, 2010 /PRNewswire via COMTEX/ -- Sangamo BioSciences, Inc. (SGMO 5.59, -0.07, -1.27%)  announced today that Edward Lanphier, Sangamo's president and CEO, will provide an update on the progress of Sangamo's ZFP Therapeutic(TM) development programs and an overview of the company's business strategy at 11:00 am ET on Wednesday, March 10, 2010 at the Cowen and Company 30th Annual Health Care Conference which will be held in Boston.

A live webcast of the presentation will be available on the Sangamo BioSciences website in the Investor Relations section http://investor.sangamo.com/index.cfm under Events and Presentations. A replay of the presentation will be archived on the Sangamo website for two weeks after the event.

LINK:

http://www.marketwatch.com/story/sangamo-biosciences-announces-presentation-at-cowen-and-company-health-care-conference-2010-03-03?reflink=MW_news_stmp
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Pepino2 on March 10, 2010, 03:25:57 pm
Cowen and Company 30th Annual Health Care Conference
Speaker: Edward Lanphier, President and CEO

Sangamo BioSciences
 (SGMO: NASDAQ)

SB-728-T Data Presentation: Due end of 2010
 Current Stock price: $5.92
52 week high: $8.75

Forecast:  Bullish :)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on May 13, 2010, 01:18:06 am
Here's an audio presentation by Sangamo at the Bank of America Merrill Lynch Health Care Conference
on Wednesday in NYC. 

The presenter talks about several of their zinc finger therapeutics, and discusses their Phase 1 HIV trials at U Penn and in San Francisco at about the 19:50 minute mark.  He said they expect to have results by the end of this year or early next year. 

https://www.veracast.com/webcasts/bas/healthcare2010/id78403470.cfm
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on July 12, 2010, 01:55:18 pm
Sangamo BioSciences Publishes Data Indicating the Use of Zinc Finger Nucleases to Generate HIV Resistant Human Stem Cells

Posted on: Mon, 12 Jul 2010 00:40:56 EDT

Sangamo BioSciences, Inc. has announced the publication of data demonstrating the preclinical efficacy of a human stem cell therapy for human immunodeficiency virus (HIV) based on its proprietary zinc finger DNA-binding protein nuclease (ZFN) technology.

In a release, the Company noted:

The ZFN approach enables the permanent disruption of the CCR5 gene, which encodes an important receptor for HIV infection, in all the cell types comprising the immune system that develop from hematopoietic stem cells (HSCs), and is the basis for a promising therapeutic strategy for the treatment of HIV/AIDS. Sangamo has two ongoing Phase 1 clinical trials to evaluate the safety and clinical efficacy of this approach in CD4+ T-cells.

The work, which was carried out in the laboratory of Paula Cannon, Ph.D., Associate Professor of Molecular Microbiology & Immunology at the Keck School of Medicine of the University of Southern California (USC), in collaboration with Sangamo scientists, was published on July 2, as an Advance Online Publication (nature.com/nbt/journal/vaop/ncurrent/full/nbt.1663.html) in Nature Biotechnology.

"These are very exciting data that provide proof of concept for a new approach to HIV treatment," said John Zaia, M.D., the Aaron D. and Edith Miller Chair in Gene Therapy and Chair of Virology, City of Hope. "The recent example of the 'Berlin Patient' who appears to have been cured of both his HIV and leukemia by receiving a bone marrow transplant (BMT) of stem cells from a donor that had a naturally occurring CCR5 mutation that makes them resistant to HIV infection, provided the model for this approach. However, the paucity of human donors with this natural CCR5 mutation and the risks of allogeneic BMT mean that we need a more practical solution to make this a therapeutic option. Modification of HSCs using ZFNs to recreate the CCR5 mutation is a potential solution."

"The data described in this paper are an important demonstration of the potential therapeutic possibilities of ZFN modification of human stem cells," said Philip Gregory, D. Phil., Sangamo's vice president of research and chief scientific officer. "We have demonstrated efficient and specific modification of human hematopoietic stem cells, rendering them resistant to infection with HIV-1 while retaining their 'stemness' and ability to differentiate. These data pave the way for the use of this technology in other diseases for which HSC modification may be therapeutically useful."

LINK:

http://www.tradingmarkets.com/news/stock-alert/sgmo_sangamo-biosciences-publishes-data-indicating-the-use-of-zinc-finger-nucleases-to-generate-hiv-resis-1033590.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: veritas on July 13, 2010, 05:46:22 am

inch,

ZFNs seem to be very credible. More research is being done in China (sort of like peer review) whereby ZFNs are being used to fight hiv with respect to integrase and transcriptase. Thus more than one way to go after hiv. However, blocking ccr5 seems to be the way to go (prevent hiv  from establishing in the first place).

I like what Sangamo is doing with respect to neuropathy also. Applications for this therapy  are endless. I wonder if it could help with lipo?

Exciting stuff.

v
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on July 13, 2010, 10:35:21 am
I Zinc Fingers too.

Can you feel the love? 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on July 13, 2010, 11:00:41 am
inch,

ZFNs seem to be very credible. More research is being done in China (sort of like peer review) whereby ZFNs are being used to fight hiv with respect to integrase and transcriptase.

v

I googled "China HIV zinc finger" and could not find anything; if by any chance you have any more info I'd love to read it.

Thanks ;)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: veritas on July 13, 2010, 04:40:06 pm

Inch,

Here's a peer review with respect to ZFNs:

http://www.biomedcentral.com/content/pdf/1741-7015-8-42.pdf

Seems you can manipulate almost any gene you desire. The above link is a better review. Let me know what you think.

v
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freaky_dream on August 21, 2010, 10:35:34 pm
New article in the LA times about a potential gene therapy being developed in conjunction with City of Hope. It involves Zinc Finger of course and injecting into the bone marrow hoping to illicit the same results as the German transplant patient who was cured of HIV. They are aiming to receive FDA approval to start trials in 3-4 years. The research was funded by a California voting initiative for Stem Cell Research (yup sometimes Californians do vote for the right things...)


http://www.latimes.com/news/science/la-sci-hiv-therapy-20100822,0,2873266.story?page=1&track=rss
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: MitchMiller on August 21, 2010, 10:50:56 pm
$100k for the treatment sounds outrageous.  By the time it's approved, many of the existing ARVs will be off patent and SHOULD be MUCH cheaper.  (I shout out those words because the US drug distribution system seems to be completely disfunctional, so it's anyone's guess if logic will prevail in a rigged marketplace.)

So this sounds like an interesting academic exercise, but I question whether it would ever have practical application given the costs.... even if it is a cure.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on August 22, 2010, 02:27:31 pm
$100k for the treatment sounds outrageous.  By the time it's approved, many of the existing ARVs will be off patent and SHOULD be MUCH cheaper.  (I shout out those words because the US drug distribution system seems to be completely disfunctional, so it's anyone's guess if logic will prevail in a rigged marketplace.)

So this sounds like an interesting academic exercise, but I question whether it would ever have practical application given the costs.... even if it is a cure.

Somehow it's hard to imagine that if this does prove to work and is a cure, functional or otherwise, it would remain an "interesting academic exercise".  How or if it's subsidized and even if the purported cost of 100k is accurate, there's no way that a proven cure will simply languish out there because it's "too expensive".  Can you imagine the hell that would be raised if news came out that a cure was discovered but too bad bastards you don't get it it costs too much?  Not going to happen.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: xman on August 22, 2010, 08:03:34 pm
No it will not happen but, as anything in this wonderful world, those in Third World Countries would be the last to benefit from this scientific conquest giving the pharmaceutical companies any possibility to exploit their meds for the maximum. I hope that a cure, even functional, would be affordable for the mass and given for free for those who can't afford it.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on September 14, 2010, 01:14:35 pm
HIV/AIDS activist Matt Sharp is taking part in the Sangamo ZFN trial:

http://aidspolicyproject.blogspot.com/2010/09/aids-activist-participates-in-clinical.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: ElZorro on September 14, 2010, 06:07:41 pm
Excellent post....let's hope the trial is successful for Matt who surely deserves to benefit after all he has been through as well as for the rest of us
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sam66 on September 14, 2010, 11:22:58 pm

  Good luck and all the best Matt,  my thoughts are with you

   sam
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on December 07, 2010, 09:36:39 am
Sangamo recently presented very good results for some of their other ZFN trials (not the HIV ones). It might be a good sign overall for this approach actually working. Time will tell.

As far as HIV, Sangamo's bio mentions that they have:

a Phase 1 / 2 clinical trial and two ongoing Phase 1 clinical trials to evaluate the safety and efficacy for the treatment of HIV/AIDS

Sangamo BioSciences Announces Data Presentation of First In Vivo Demonstration of ZFN-mediated Gene Correction Via Systemic Delivery at American Society for Hematology Meeting

LINK:

http://www.prnewswire.com/news-releases/sangamo-biosciences-announces-data-presentation-of-first-in-vivo-demonstration-of-zfn-mediated-gene-correction-via-systemic-delivery-at-american-society-for-hematology-meeting-111435574.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on December 16, 2010, 01:23:24 pm
Here's a video report showing Matt Sharp talking about his gene therapy treatment.

Bone marrow transplant may hold cure to HIV

LINK:

http://www1.whdh.com/news/articles/national/12003012488744/bone-marrow-transplant-may-hold-cure-to-hiv/

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: veritas on December 16, 2010, 03:53:29 pm

Inch,

You know everyone is watching this one. To release "any" information this early is certainly a good sign.

Let's hope this is it and end this damn disease.

Nice find!

v
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on December 16, 2010, 04:09:09 pm
Inch,

You know everyone is watching this one. To release "any" information this early is certainly a good sign.

Let's hope this is it and end this damn disease.

Nice find!

v

I suspect that altering CCR5 via gene therapy may not be enough and that at least some chemo and radiation would be necessary, a milder version of the regular "conditioning" involved in standard bone marrow transplants.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: wtfimpoz on December 18, 2010, 01:14:19 pm
I've been mulling over this response for a while now.  Before we get excited about Matt Sharp's amazing reaction to his refurbished cd4 cells, lets remember the source-as a member of Project Inform, he's biased towards and prone to selling cutting edge research.  "I've seen my T-cell count double" is an exact quote he's used before, in testimony of selzentry.  Further, the glaring omission of his viral load screams out that his this treatment is far from a "functional cure".  From what I read of Sharp, he has my utmost admiration.  He's done marvelous things to advance the cause of a cure and improve the lives of pozzies on both a scientific and practical level.  I worry however that the current excitement about a cure might overheat and burn out before its practical, or lead to a sense of complacency that its inevitable.  Let's wait for the results at CROI before we start getting excited.  Thanks everyone for your time and attention, and thank you Inchling for your dilligent attention to these issues.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on December 18, 2010, 01:25:38 pm
wtf, I basically agree with what you say above.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: veritas on December 18, 2010, 03:40:52 pm

WTF,

Your words of caution are well placed. Of course, all should wait for the final results to celebrate. However, what makes Matt's words encouraging is the timing ( very early into the trial). I must also take into consideration that he must have gotten the ok from those running the trial to release some of his results early, although, not too specifically. Also, he alludes to viral load , with the statement:

"From the experiment so far my T-cells have doubled, my percentage numbers are up, everything is going in the right direction," he says.".

Definitely , one to keep an eye on.

When viewing these studies, reading at arms length should be the rule. However, never lose hope!





Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on December 19, 2010, 08:12:47 pm
Is it supposed to work like this? :  He's stopped taking any meds, HIV will attack his unmodified T-Cells and replicate, raising his VL.   Over time, this will kill off his unmodified T-Cells.  Only his modified / resistant T-Cells will remain.  HIV eventually will find no foothold.  So his viral load will go up at first and then go down. 

Just seeing if I understand how the mechanism is supposed to work.  Is this about right?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: wtfimpoz on December 20, 2010, 01:49:04 am
Thats kinda what I'm thinking, but its never that simple.  For starters, there's still the possiblity of a chronic HIV brain infection.  Second, I'm not sure if the modified cd4 cells are as long lived as normal ones, or if they're capable of replicating on their own or if someone who'se been "functionally cured" is going to need a booster every few months. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: lmdo on December 20, 2010, 08:39:28 pm
It's like we need to harvest some stem cells, nurture them into T cells, with the gene alteration, then keep them for top ups if and when they are needed.

Mmmmm. I am Certain that if this were a feasible concept it would be being investigated. But can I have a gold star for trying?

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on December 22, 2010, 10:17:41 am
The last few posts have degenerated into ridiculous and speculative gobbly gook.  Give it a rest.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on January 10, 2011, 11:42:41 am
Tucked into Sangamo's press release regarding Diabetic Neuropathy is the timing of preliminary results from the SB-738-T trials:

"In addition, in the first quarter of 2011, we expect to have preliminary data from the two ongoing Phase 1 trials of our ZFN-based Therapeutic, SB-728-T for the treatment of HIV/AIDS."

Here are the relevant paragraphs and the link:

http://www.prnewswire.com/news-releases/sangamo-biosciences-announces-completion-of-enrollment-of-phase-2b-clinical-trial-in-diabetic-neuropathy-113192164.html

SB-728-T

Sangamo is developing SB-728-T, a ZFN approach to the treatment of HIV/AIDS and has an ongoing Phase 1/2 and two Phase 1 clinical trials to evaluate the safety and clinical efficacy of this approach in CD4+ T-cells. Sangamo's ZFNs are designed to permanently modify the DNA sequence encoding CCR5, a co-receptor that enables HIV to enter and infect cells of the immune system. Individuals carrying a naturally occurring mutation of their CCR5 gene, a variant known as CCR5-delta32, have been shown to be resistant to HIV infection.  Building on this observation, a study published in Blood in December 2010 reported an effective cure when an AIDS patient with leukemia received a bone marrow transplant from a "matched" donor with this delta-32 CCR5 mutation. This approach transferred the HSCs residing in the bone marrow from the delta-32 donor, and provided a self-renewable and potentially lifelong source of HIV-resistant immune cells. After transplantation, the patient was able to discontinue all anti-HIV drug treatments, CD4 counts increased, and viral load dropped to an undetectable level, demonstrating effective transplantation of protection from HIV infection.

As part of a collaboration with scientists at City of Hope and the University of Southern California, under a $14.5 million CIRM Disease Team Research Award, Sangamo is also developing an approach to modify a patient's own hematopoietic stem cells (HSCs) to circumvent the need to find matched donors that carry the delta-32 CCR5 mutation and while providing a renewable and long-lasting source of HIV-resistant cells. Specifically, the grant funds the development of a ZFN approach to treat AIDS patients by first isolating their HSC, modifying them using CCR5-specific ZFNs, and then re-infusing them to reconstitute the immune system with CCR5-negative, HIV-resistant immune cells.  Sangamo and its collaborators will provide an update of preliminary clinical data of SB-728-T as well as the preclinical stage program in HSCs in the first quarter of 2011.

"We begin 2011 with a solid foundation of commercial and technical successes and look forward to a year of significant clinical progress," commented Mr. Lanphier. "By the end of the year, we expect to have data from the Phase 2b clinical trial (SB-509-901) of our lead ZFP Therapeutic, SB-509 in DN, which will allow us to move forward with our partnering discussions.   In addition, in the first quarter of 2011, we expect to have preliminary data from the two ongoing Phase 1 trials of our ZFN-based Therapeutic, SB-728-T for the treatment of HIV/AIDS.  Finally, we look forward to advancing our extensive preclinical pipeline as well as participating in the continued commercial expansion of our ZFP technology through our partnerships in plant agriculture and in the growing area of research reagents, cell line engineering and transgenic animal model production."

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on January 14, 2011, 08:25:07 pm
This stock has been going nuts over the last month or two in no small part because of the buzz related to the ongoing HIV trials.  Perhaps it's hype, but the institutional buyers are now making their presence known and I find that fascinating.  Their upcoming presentations at CROI and others will be ones to watch.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 03, 2011, 11:51:10 am
This is long -- but it's pretty juicy.  From Edward Lanphier on Sangamo earnings call yesterday.   They will be having 4 presentations at CROI in early March on (I think) Carl June's study, their own studies of aviremic and viremic population, USC/Keck/Paula Cannon's work and work on targeting CXCR4 receptor.

Here's the link:
http://seekingalpha.com/article/250427-sangamo-biosciences-ceo-discusses-q4-2010-results-earnings-call-transcript

And the juicy bits:

"I would now like move on to our novel approach to the treatment of HIV/AIDS and the strategy and rationale that we have employed is we've moved this product into clinical trials.
In addition to our two ongoing Phase 1 trials from which we will present preliminary data at CROI, we have initiated a Phase 1/2 trial in HIV in subjects who are not currently on antiretroviral therapy or HAART.
With the initiation of this trial, we are evaluating our ZFN-modified T-cell approach in the full range of HIV-infected patients, from those early in their infection who are not on HAART all the way through to those patients who are failing HAART."

[Discussion of HIV, elite controllers, CCR5, and the Berlin Patient]... "And three years later, this person is both cancer-free and free of HIV.

Our ZFN technology allows us to mimic this outcome. Specifically, by editing the CCR5 gene, we hope to create T-cells that will be protective from HIV infection and capable of mounting an immune response not only to opportunistic infections, but also to HIV itself, potentially enabling a functional cure in these patients analogous to an elite controller.

There are now three clinical trials ongoing, two Phase 1 trials and a Phase 1/2 trial. Our strategy is to evaluate this product across the spectrum of HIV infection from those who are treatment-naïve, meaning those who are infected with the virus but who are not yet on drugs and also still have a strong immune system, to subjects who are being successfully treated on HAART and are therefore aviremic but who may have a lower or deteriorating CD4 T-cell count through a smaller group of subjects who are failing on HAART who have become viremic again and have rapidly deteriorating CD4 T-cell counts.

Our strategy has been to initially begin to evaluate SB-728-T in Phase 1 trials in the aviremic population, subjects on HAART who have well controlled and detectable virus. In the trial that we are conducting in collaboration with Carl June at the University of Pennsylvania and our own trial, the SB-728-902 trial, we're focused on this aviremic population.

Our initial clinical observations of the pharmacology of the modified T-cells have been encouraging, which is why we have now moved into the viremic population at both ends of the spectrum with expansion of our Phase 1 trial into HAART failures and the initiation of the Phase 1/2 trial, SB-728-T-1002, in treatment-naïve subjects. Both of these populations will allow us to not only look at changes in the immune system, but also the impact of the virus on the modified T-cell product.

As I mentioned earlier, I'm very pleased to say that preliminary data from the two Phase 1 clinical trials will be presented in oral presentations at the beginning of March at CROI in Boston. We will have a total of four oral presentations and two of them will focus on these initial clinical studies.
So what data can you expect from these Phase 1 studies? The questions that we are asking in these studies are the following: how do these modified cells behave; are they safe; do they disappear; do they expand; do they traffic like normal T-cells? These are basic questions that need to be answered before moving on to ask more complex questions. These data will give us a strong sense of whether ZFN-modified cells have the potential to mimic an elite controller phenotype.

In addition, we'll also look at the overall effect that the modified cells have on a subject's own immune system. If we are creating a compartment of the immune system that it is protected from HIV infection and is immune-confident, what effect could that have on the rest of the immune system and specifically the total CD4 count?

There will be introduction of these modified cells effect to CD4, CD8 ratio, which is a direct indication of immunological confidence. Improvement in these factors would speak directly to the primary immunological defect for the HIV, destruction of CD4 T-cells. We look forward to discussing these data with you in detail in early March.

The next generation of our HIV program employs the same CCR5-specific zinc finger nucleases, but in hematopoietic stem cells. T-cells are internally differentiated cells and while they can expand and circulate for a very long time, they have a life span of just a couple of years. In contrast, the function of hematopoietic stem cells is to continue to produce cells of the immune system and last for a lifetime.
And so using zinc finger nucleases in hematopoietic progenitors, we can potentially protect the entire immune system analogous to the Berlin patient's result with every immune system cell begin CCR5-negative. Along with our academic collaborators, we are funded by a $14.5 million grant from the California Institute for Regenerative Medicine to push this forward. This work is going very well and will also be the subject of a podium presentation at CROI.

Our fourth oral presentation will focus on yet another receptor involved in HIV infection, the CXCR4 receptor, which again is a target that can be disrupted by our ZFN technology. So a lot going on at CROI and as I said earlier we look forward to discussing these data with you in detail in early March.
And with that update on our diabetic neuropathy and HIV programs, I'm going to ask Philip to provide you with an additional example of data that will illustrate the broad power of our technology platform."
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 10, 2011, 07:21:03 pm
Bloomberg Businessweek had a story today on Sangamo:

http://www.businessweek.com/magazine/content/11_08/b4216018308281.htm

Juicy parts: 

21 people involved in two studies

and

"This approach shows the most promise of any that I know of," says Jay A. Levy, a researcher at the University of California in San Francisco who helped identify HIV as the source of AIDS in 1984. "It's a terrific way of looking for a long-term functional cure for the virus."

and

One person who hopes it will prove effective is Matt Sharp, 54, an AIDS educator who was diagnosed in 1988 and today takes a daily regimen of three antivirals. He learned about the Sangamo trial a year ago and enrolled. Since last summer, when Sharp received an infusion of his own gene-modified T-cells, blood cells that help the immune system fight infection, the number of those cells has doubled, he says. "I'm just hoping I could get an infusion once a year that would keep HIV under control and I won't have to deal with the effects of taking medication."


Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on February 10, 2011, 07:24:57 pm
Thanks for the updates. ;)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on February 17, 2011, 09:27:48 pm
Here's a 3 minute news clip from last week about Sangamo's clinical trial.

http://www.bloomberg.com/video/66655208/
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: georgep77 on February 18, 2011, 04:34:18 pm
Here's a 3 minute news clip from last week about Sangamo's clinical trial.

http://www.bloomberg.com/video/66655208/
OMG !  cross fingers everybody !

                       :D
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Gio on February 18, 2011, 07:45:16 pm
trying to hold my enthusiasm like the LTSs' said there is always a hidden cost.. but i am hopeful crossing my fingers.  Thank you Inch for the updated link
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: surf18 on February 18, 2011, 11:36:46 pm
sounds great. lets fast track this!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sensual1973 on February 19, 2011, 03:23:09 am
Great stuff,lets hope to hear the good results real soon.

"we want to live free of meds".
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on February 19, 2011, 10:51:05 am
One thing I did not realize, which came up in that video by both the reporter as well as the guy from Sangamo, is that  in addition to HIV not having a doorway to enter the altered CD4 cells lacking CCR5, these cells would then be free to actually fight off HIV.

The video has a clip from Timothy Brown, who I think looked and sounded good. I guess he's moved back to the USA. I wonder what he's doing as far as health insurance. Maybe he's such a special case that research institutions would see him for free.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hellraiser on February 19, 2011, 12:44:05 pm
One thing I did not realize, which came up in that video by both the reporter as well as the guy from Sangamo, is that  in addition to HIV not having a doorway to enter the altered CD4 cells lacking CCR5, these cells would then be free to actually fight off HIV.

The video has a clip from Timothy Brown, who I think looked and sounded good. I guess he's moved back to the USA. I wonder what he's doing as far as health insurance. Maybe he's such a special case that research institutions would see him for free.



This is something that I was wondering about too.  Another thing that I was curious about was how long do these CD4 live?  If I remember basic biology your CD4 cells are created in your bone marrow which is why to produce them on your own you have to have a blood marrow transplant.  Then the altered bone marrow is producing CD4 cells without the CCR5 receptor.  Otherwise won't we have to get these infusions of genetically altered cells on a regular basis until the virus is somehow completely eradicated from the body?  This is of course assuming that THAT will eventually happen if we go off ART and the reservoirs deplete themselves while the altered CD4s clean up the mess.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 19, 2011, 01:16:43 pm
As near as I can make out, Matt Sharp and the 21 people in the trial are part of a modified T-Cell trial. Here's what Ed Lanphier said about that (above, but quoting the relevant part):

"The next generation of our HIV program employs the same CCR5-specific zinc finger nucleases, but in hematopoietic stem cells."

Meaning that the current program is using T-Cells, not stem cells (I think).  He then goes on to describe the difference:

"T-cells are internally differentiated cells and while they can expand and circulate for a very long time, they have a life span of just a couple of years. In contrast, the function of hematopoietic stem cells is to continue to produce cells of the immune system and last for a lifetime."

So it seems T-Cells last several years, hematopoietic stem cells are forever. He continues:

"And so using zinc finger nucleases in hematopoietic progenitors, we can potentially protect the entire immune system analogous to the Berlin patient's result with every immune system cell begin CCR5-negative. Along with our academic collaborators, we are funded by a $14.5 million grant from the California Institute for Regenerative Medicine to push this forward. This work is going very well and will also be the subject of a podium presentation at CROI."

I think this last part is the work with Paula Cannon and USC's Keck school.  I'm clearly no expert, but I think the progenitors are stem cells that create T-Cells, macrophages, etc. All of them would be CCR5 negative.  That would be huge.  Their presenting this work as well at CROI about two weeks from now.

One think I still don't understand is that Timothy Ray Brown -- bless him! -- had both R5 and X4 virus.  I don't really understand why the X4 virus disappeared as well. 

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hellraiser on February 19, 2011, 01:29:17 pm
His entire immune system was wiped out.  Assuming for the moment that the reservoirs reside solely in immune cells this might be one explanation.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 22, 2011, 12:09:31 pm
Here's a link to the CROI presentations (the conference begins on Sunday). 

http://zika.retroconference.org/croi-2011-pocket-program.pdf

Here are the relevant sessions:

Session 46 (Monday, 10:00-10:15)
Successful and Persistent Engraftment of ZFN-M-R5-D Autologous CD4 T Cells (SB-728-T) in Aviremic HIV infected Subjects on HAART
Jay Lalezari, R Mitsuyasu, S Deeks, S Wang, G Lee, M Holmes, P Gregory, M Giedlin, W Tang, and D Ando
Quest Clin Res, San Francisco, CA, US; Univ of California, Los Angeles, US; Univ of California, San Francisco, US; and Sangamo Biosci Inc, Richmond, CA, US

Session 47 (Monday, 10:15-10:30)
Creating an HIV-resistant Immune System: Using CXCR4 ZFN to Edit the Human Genome
Craig Wilen, J Wang, J Tilton, J Miller, S Sherrill-Mix,F Bushman, P Gregory, C June, M Holmes, and R Doms
Univ of Pennsylvania, Philadelphia, US and 2Sangamo Biosci Inc, Richmond, CA, US

Session 164 (Wednesday Symposium, 4-6)
CCR5 Knock-out in Hematopoietic Stem Cells
Paula Cannon, N Holt, U Hofer, C Exline, J Wang, P Gregory,and M Holmes
Univ of Southern California, Los Angeles, US and Sangamo Biosci Inc, Richmond, CA, US

Session 165 (Wednesday Symposium, 4-6)
Disruption of CCR5 in Zinc Finger Nuclease-treated CD4 T Cells: Phase I Trials
P Tebas, B Levine, G Binder, J Hoxie, R Collman, P Gregory, M Holmes, D Ando, and Carl June
Univ of Pennsylvania, Philadelphia, US and 2Sangamo Biosci Inc, Richmond, CA, US


Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 25, 2011, 08:24:05 pm
Well...I'm excited to see Monday's trial data.  Here's a presentation from Ed Lanphier, Sangamo.   He says "functional cure" repeatedly, and seems to be confident of the data he'll presenting at CROI.    Crossing my fingers and toes here in Nor Cal.

http://www.marketwatch.com/video/asset/sangamos-functional-cure-for-hiv-2011-02-25/5A7B3B21-69D3-4832-AF2F-28DC64876355#!5A7B3B21-69D3-4832-AF2F-28DC64876355
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on February 26, 2011, 08:36:53 pm
Yeah he seems really confident. I hope this works and a functional cure does happen soon!!

It does sound like this will be the next big thing and change the way HIV is treated completely but what do I know? Maybe I am getting ahead of myself...

I'm pretty newly diagnosed and don't really know too much about HIV cure news and methods, but for those that have been diagnosed longer than me and have experience, what do you guys think about this method of defeating HIV? Do you guys have faith in this method and believe it is possible, or does it sound like just another "mumbo-jumbo" news story that will fail?  Has any similar type of study failed in the past? 



Please fill me in.....Thanks
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: zadex on February 27, 2011, 11:28:21 am
Personally, I think this is hopeful.
It is not about eradication of the virus, but it could still be huge.
This short overview of Sangamo's ZFP work (from an investor) is pretty balanced:
http://sobekanalytics.com/yahoo_site_admin/assets/docs/sangamo_CROI_pre.5090727.pdf
But you also have to keep in mind that there will be a long process before it becomes available (that would be a few years away).
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: georgep77 on February 27, 2011, 12:14:12 pm
But you also have to keep in mind that there will be a long process before it becomes available (that would be a few years away).

accord to Sangamo's CEO Edward Lanphier probably 10 years

                                     :(
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sensual1973 on February 27, 2011, 09:27:50 pm
its always 10 years and after 10 years there is another 10 years,reminds me of the donkey and the carrot.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: zadex on February 28, 2011, 02:45:09 pm
More good news:
http://www.biospace.com/news_story.aspx?StoryID=212048&full=1
The data looks very promising. The two things to look for (CD4/CD8 ratio & how the modified T cells "traffic")
show what we would hope to see.  In addition, these modified cells
"were observed to undergo selective expansion in the gut mucosa, a major reservoir of virus in the body, suggesting, as predicted, that the cells were resistant to HIV infection. These data represent the necessary first steps in the development of a "functional cure" for HIV/AIDS by providing a protected CD4+ T-cell population in these subjects that is resistant to HIV infection."
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Gio on February 28, 2011, 03:01:40 pm
I just read the news myself.  I definitely wouldnt mind being part of the larger study... 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on February 28, 2011, 08:27:24 pm
Not sure what she is basing this on, but:

 If the therapy cuts HIV levels in patients who aren’t taking antiviral drugs, it may gain approval by late 2013, said Liana Moussatos of Wedbush Securities in San Francisco.

LINK:

http://www.bloomberg.com/news/2011-02-28/sangamo-gene-therapy-shown-to-be-safe-in-first-study-in-hiv.html

The article in Poz is very informative:

http://www.aidsmeds.com/articles/HIV_Sangamo_CCR5_1667_19952.shtml
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on February 28, 2011, 08:36:19 pm
I'm hoping and praying!!!!!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on March 02, 2011, 12:05:52 am
I *think* this is the link to Dr. Lalezari's presentation yesterday --

http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20445&&dp=player.jsp&e=13711&mediaType=podiumVideo

It make take a few years, but I think this may really happen -- we get our stem cells conditioned, we get an infusion of modified stem cells, they graft...we have an immune system than can resist HIV.  Paula Cannon's presenting her stem cell work in mice tomorrow.  Should be interesting.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: BobF on March 02, 2011, 01:14:55 am
But isn't it true that the current memory long-term cells that are already infected don't die, and can continue to reproduce when activated?  If so, it suggests this "cure" is really just another treatment and it's unknown how long the improvement might last........
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on March 02, 2011, 10:11:08 am
But isn't it true that the current memory long-term cells that are already infected don't die, and can continue to reproduce when activated?  If so, it suggests this "cure" is really just another treatment and it's unknown how long the improvement might last........

Thanks for that note of optimism, Bob.  Probably a good idea to read through the research and listen to the interviews to educate yourself.  This is all about (as I understand it) permanently modifying T cells and hematopoietic stem cells, thus building a separate immune system that can't be infected by the virus; similar to the "Berlin Patient", Tim Brown, and the select minority of folks who lack the CCR5 receptor.  If the virus can't infect host cells, it dies out.  Assuming they are able to do this, and the work so far is indicating proof of concept, then indeed it will lead to a "cure", functional or otherwise.  I'm not clear on your assertion that this will likely be a "treatment" akin to HAART.  How did you draw that conclusion?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on March 02, 2011, 11:50:57 am
Here's an exciting 4 min interview with Dr. Lalezari --
http://www.everydayhealth.com/hiv-aids/0301/experimental-hiv-treatment-promising.aspx

As he says, the results talked about on Monday were with people whose VL was undetectable.  The new cells grew and expanded more than they expected.  Dr. L says in treatment-naive patients *with* VL, the new cells should do even better (should "flourish") because they have a selective advantage since HIV goes after the non-modified cells.  This will be done in the next round of trials. If this does NOT reduce VL in viremic people, well, then this was a nice experiment.  But if it does, that'll be a "whole new universe", accoding to Dr. L.  Good stuff!

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on March 02, 2011, 08:07:36 pm
I *think* this is the link to Dr. Lalezari's presentation yesterday --

http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20445&&dp=player.jsp&e=13711&mediaType=podiumVideo

It make take a few years, but I think this may really happen -- we get our stem cells conditioned, we get an infusion of modified stem cells, they graft...we have an immune system than can resist HIV.  Paula Cannon's presenting her stem cell work in mice tomorrow.  Should be interesting.

Does anyone have a link to Paula's presentation or info on the outcome of it? Can't find it anywhere...
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on March 02, 2011, 09:09:24 pm
Here's an exciting 4 min interview with Dr. Lalezari --
http://www.everydayhealth.com/hiv-aids/0301/experimental-hiv-treatment-promising.aspx

As he says, the results talked about on Monday were with people whose VL was undetectable.  The new cells grew and expanded more than they expected.  Dr. L says in treatment-naive patients *with* VL, the new cells should do even better (should "flourish") because they have a selective advantage since HIV goes after the non-modified cells.  This will be done in the next round of trials. If this does NOT reduce VL in viremic people, well, then this was a nice experiment.  But if it does, that'll be a "whole new universe", accoding to Dr. L.  Good stuff!


"The cells are homing in to the gut mucosa."

I get so turned on by all this medical talk.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tim Horn on March 02, 2011, 09:20:46 pm
Paula Cannon's presentation this afternoon in Boston was exceptionally informative -- not only is her work truly novel, she is also a wonderful communicator.

You'll be able to access Cannon's talk -- the whole informative session entitled "Obstacles to a Cure" -- either later tonight or tomorrow morning:

http://www.retroconference.org/2011/data/files/webcast_2011.htm

Dr. Cannon didn't really present any "new" data from her studies involving humanized mice, but rather a detailed overview of the work she's been doing for the past several years. For a really great read on this work -- perhaps in anticipation of viewing her talk online -- I highly recommend the following:

http://www.technologyreview.com/biomedicine/25563/ (http://www.technologyreview.com/biomedicine/25563/)

Tim
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tim Horn on March 02, 2011, 09:38:24 pm
bI'm not clear on your assertion that this will likely be a "treatment" akin to HAART.  How did you draw that conclusion?

This has been raised a a few times in this thread, but it's important to stress that the Phase I data presented by Dr. Lalezari truly is a "treatment" approach... akin to HAART, so to speak. Simply removing mature CD4+ cells from a person living with HIV, exposing the cells to an adenovirus containing zinc fingers, and then reinfusing the expanded cells isn't likely to be a cure. We hope it will create a long-lived population of HIV-resistance cells -- which should help reduce viral load, increase CD4s and potentially allow people to either delay or stop ARV therapy (though the virus will still be there) -- but a much more extreme course of treatment would be needed for a cure.

Curing HIV using zinc fingers -- or other gene therapies in development -- will likely require treating collected stem cells (which eventually form into CD4 cells) and basically wiping out the existing immune system (including memory CD4 cells infected with HIV) and rebuilding the immune system using the genetically modified stem cells. This is not what Lalezari's study did -- it is what researchers at City of Hope are currently exploring in HIV-positive patients with relapsing lymphoma and other researchers hope to try, eventually, in other populations of people living with HIV. This won't be easy -- or even ethical in a number of situations -- given that the pre-transplant "conditioning" therapy is brutal and potentially lethal and will likely only be tried, at least initially, in individuals for whom death would otherwise be imminent.

While Lalezari's work is truly remarkable on a treatment level alone, the various key findings of the study -- that the transplant process is safe, that a large number (~26%) of cells treated in the lab successfully lose their CCR5 receptor, that the cells not only survive but thrive after being infused (at least for 90 days) and that the cells successfully migrate to major reservoirs of virus in the body (e.g., the gut) -- also suggest that we can move into curative research, using this approach, with a fair amount of confidence.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on March 03, 2011, 12:34:55 am
I just watched Dr. Cannon's and Dr. June's presentations (they are the third and fourth presenters) --

http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20445&&dp=player.jsp&e=13748&mediaType=podiumVideo

I was also struck by the therapeutic potential of the T-Cell treatment (as opposed to the stem cell treatment).  Particularly tantalizing is the slide at 01:51:41 in which Dr. June shows the viral load of two patients during a structured treatment interruption at day 28 for 12 weeks.  The virus comes back, and then it begins to decline BEFORE HAART is restarted.  He says this evidence is "anecdotal" at this point.  The first questioner in the Q&A asks a follow up about this -- Dr. June said the cause of the decline is still TBD.  Keeping my fingers crossed that it's due to viral selection/ some immunity due to the modified T-Cells.  He said that this is being investigated right now. 

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: BobF on March 03, 2011, 02:00:16 am
Gee Freewillie - maybe you're the one who should educate yourself.   I'm apparently correct per Tim's note below.   I was just asking the question, but sadly you jumped to an attack indicating my apparent lack of optimism and saying I should educate myself.  That is what I was attempting to do, but some equate questions with pessimism I guess.  LoL.


This has been raised a a few times in this thread, but it's important to stress that the Phase I data presented by Dr. Lalezari truly is a "treatment" approach... akin to HAART, so to speak. Simply removing mature CD4+ cells from a person living with HIV, exposing the cells to an adenovirus containing zinc fingers, and then reinfusing the expanded cells isn't likely to be a cure. We hope it will create a long-lived population of HIV-resistance cells -- which should help reduce viral load, increase CD4s and potentially allow people to either delay or stop ARV therapy (though the virus will still be there) -- but a much more extreme course of treatment would be needed for a cure.

Curing HIV using zinc fingers -- or other gene therapies in development -- will likely require treating collected stem cells (which eventually form into CD4 cells) and basically wiping out the existing immune system (including memory CD4 cells infected with HIV) and rebuilding the immune system using the genetically modified stem cells. This is not what Lalezari's study did -- it is what researchers at City of Hope are currently exploring in HIV-positive patients with relapsing lymphoma and other researchers hope to try, eventually, in other populations of people living with HIV. This won't be easy -- or even ethical in a number of situations -- given that the pre-transplant "conditioning" therapy is brutal and potentially lethal and will likely only be tried, at least initially, in individuals for whom death would otherwise be imminent.

While Lalezari's work is truly remarkable on a treatment level alone, the various key findings of the study -- that the transplant process is safe, that a large number (~26%) of cells treated in the lab successfully lose their CCR5 receptor, that the cells not only survive but thrive after being infused (at least for 90 days) and that the cells successfully migrate to major reservoirs of virus in the body (e.g., the gut) -- also suggest that we can move into curative research, using this approach, with a fair amount of confidence.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: bmancanfly on March 03, 2011, 02:52:06 pm
 :-X
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on March 03, 2011, 10:14:49 pm
Not to split hairs but based on everything I've read (which is a lot), including Tim's eloquent words above, this treatment (and other similar gene therapies aimed at eliminating CCR5 and CXCR4), if successful, would not be "akin to HAART."
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: BobF on March 04, 2011, 11:48:58 pm
But the point I've been questioning, to clarify, is that it would require the complete destruction of the immune system and then the gene therapy treatment, otherwise it's not possible to kill 100% of the currently infected long-term cells.   This step would be deadly to many, has major medical issues associated, etc.    I'm not trying to discount the positives that the treatment approach appears to suggest, just clarify that a complete cure isn't the likely outcome.

Not to split hairs but based on everything I've read (which is a lot), including Tim's eloquent words above, this treatment (and other similar gene therapies aimed at eliminating CCR5 and CXCR4), if successful, would not be "akin to HAART."
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on March 05, 2011, 12:43:12 am
But the point I've been questioning, to clarify, is that it would require the complete destruction of the immune system and then the gene therapy treatment, otherwise it's not possible to kill 100% of the currently infected long-term cells.   This step would be deadly to many, has major medical issues associated, etc.    I'm not trying to discount the positives that the treatment approach appears to suggest, just clarify that a complete cure isn't the likely outcome.


The idea is to recreate the success of Timothy Brown but without having to ablate immune cells. It's too early to know how it will play out.

It's possible that, if necessary, a milder and more tolerable amount of cell conditioning could do the trick.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tim Horn on March 05, 2011, 08:25:16 am

It's possible that, if necessary, a milder and more tolerable amount of cell conditioning could do the trick.

Inchling makes a good point.

One of the lingering questions regarding Timothy Brown's case is which treatment (chemo vs. the gene-modified stem cell infusion) did what. While there's no doubting that his pre-transplant conditioning did a lot of the heavy lifting in terms of killing off HIV-infected CD4s, monocytes and macrophages in his body, it's also possible that the HIV-resistant stem cells (some of which gradually matured into HIV-resistant CD4s) helped finish the job of clearing lingering virus. In fact, one study at City of Hope is attempting to explore whether its chemo, the genetically modified cells or a combination of both that leads to eradication.

If it turns out that genetically modified cells play a significant role in getting into the nooks and crannies of the immune system where HIV hides, then the possibility of achieving a cure without full-on destructive ablation -- perhaps using "chemo lite" of even a short course of potent ARV therapy -- becomes plausible.

Also consider that we might be able to achieve a functional cure for HIV in a much larger percentage of individuals, as opposed to a full-on sterilizing cure that may very well require ablation to rid the body of  HIV-infected CD4s. In other words, a situation in which HIV remains present in the body, but without the need for chronic antiretroviral therapy to keep viral load low and CD4s high.

Supposing we were able to infuse a large number of CD4s (or CD4 progenitor cells) deficient in the genes responsible for expressing both CCR5 and CXCR4 and that those cells continued to expand and essentially last a lifetime? For all intents and purposes, this could create a sizable reservoir of CD4s remaining permanently resistant to HIV, keep viral load low and the immune system healthy.

This, of course, comes with some important questions.

First, is it even safe to knock out the gene responsible for CXCR4 production? There's plenty of data showing that people can survive and thrive without the CCR5 receptor. Much less is known about the CXCR4 receptor and there's really no known population of individuals lacking this receptor to even suggest that it can be knocked out (or even blocked using drugs) without deleterious effects.  

Second, as we've seen in a growing number of studies, even low levels of HIV in the body are associated with some degree of chronic immune activation and inflammation, which seems to be playing a role in the higher risk of things like cardiovascular disease and cancers in people living with the virus. Thus, how much of a functional cure is truly necessary to allow for people to remain off ARV treatment and expect normal lifespans?

Lots and lots of questions and it's so hard to even think about answers based on what very little we've seen thus far. But it's truly remarkable that we're even in a position to begin thinking about these questions -- it wasn't too long ago that researchers would dare ponder them openly (let alone get grant money to explore these questions), much like they're doing now.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Gio on March 05, 2011, 08:36:12 pm
Someone explain this too me...  i heard the bloomberg article indicating that if it works (which it did) that it is possible for Sangamo to get approval in a couple of years.  From what i read Sangamo has already started a phase I/II study to see what groups or subgroups get the best benefit..  As for the stock my god it has gone up considerably.. Any thoughts whether the statement by the reporter correct?  I get the feeling from what i have read here that it will take more time then the media is reporting
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on March 05, 2011, 09:35:52 pm
Someone explain this too me...  i heard the bloomberg article indicating that if it works (which it did) that it is possible for Sangamo to get approval in a couple of years.  From what i read Sangamo has already started a phase I/II study to see what groups or subgroups get the best benefit..  As for the stock my god it has gone up considerably.. Any thoughts whether the statement by the reporter correct?  I get the feeling from what i have read here that it will take more time then the media is reporting

I hope this will be available in a few years if it works after the next phase or two, but I'm unsure....I'm guessing it may take longer but who knows? You know how these things go....But as always I'm hoping for the best.


I think the article also said they are currently recruiting for the next phase, but does anyone know when the next phase will begin? And how many weeks till we get the results?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tim Horn on March 05, 2011, 11:19:07 pm
First off, I haven't read anything that suggests SB-728-T may be approved by the FDA in the next few years. If a publication did report this, it's erroneous at best. A lot of the research that's going on now (two Phase I studies and one Phase I/II study) is being undertaken to answer some fairly basic questions before the company begins to plan larger safety and efficacy trials.

One issue to consider -- a lot of conversations are going to need to take place with the FDA, notably its biologics division (which differs considerably from its drug division), to determine how this drug should be studied and what the safety and efficacy objectives should be.

Another issue to consider -- Sangamo is waiting to see if the adenovirus vector it uses to expose the CD4 cells to SB-728-T is, in fact, the best vector to use. Keep in mind, one of the six patients treated in the first two cohorts of the Phase I study reported by Dr. Lalezari mounted a potent immune response to the adenovirus used, which greatly limited the activity of the reinfused cells. If this happens in the other cohorts now being studied in the Phase I, or in the other two ongoing studies, it's possible that Sangamo may want to repeat the tests again, using a different vector, in order to maximize potential effectiveness before going into Phase II and Phase III studies.

With respect to the "next phase," you're probably referring to two additional cohorts in Lalezari's ongoing study -- one cohort will consist of six patients who will receive a transplant of 30 billion CD4 cells (10 billion and 20 billion cells were transplanted in the first two cohorts and a second cohort consisting of two to four patients with multi-drug-resistant virus. The only other studies going on right now (both are fully enrolled) is another six-patient Phase I study being conducted at the University of Pennsylvania (looking at what happens when standard antiretroviral treatment is stopped) and a Phase I/II study involving 14 patients who have either not yet started ARV treatment or have stopped ARV treatment.

While I'm sure Sangamo is eager to move into larger studies -- we all are -- pitting SB-728-T against standard ARVs, the company (along with the FDA) is undoubtedly waiting for the results of the small studies now under way. Remember, gene therapy has a checkered history and there's no way the FDA is going to rush this treatment (or cure) approach into large clinical trials or through approval without a serious amount of scrutiny.   
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: coolstone25 on March 06, 2011, 07:45:08 am
Hello Tim

isn't there talk of usage of a different vector (Lentiviral) within Sangamo already? The responses to and using Ad vectors had some questions raised already.

Also, although the approval is going to invite serious scrutiny, I think there's pressure within the administration, for advances in therapeutics especially for people who aren't responsive to any medications. The approval is (safely assumed) well on it's way. ;)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: zadex on March 06, 2011, 10:48:17 am
Apparently, 50 % of people have antibodies to the adenovirus vector, so another vector may be used
http://www.thebodypro.com/content/art60675.html

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Gio on March 07, 2011, 09:13:49 am
Tim thank you for the clarification
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on March 10, 2011, 08:42:37 pm
 -- really, any cure would be just fine :) --

Exploring HIV Gene Therapy at CROI 2011
Filed under: VIRxSYS — virxsys @ March 7, 2011
Tessio Rebello, our Vice President of Clinical Affairs, just got back from the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, MA. Although this year, VIRxSYS chose not to do a formal presentation of data, our attendance allowed us the opportunity to take meetings with several key thought leaders where we received praise for our research and forward-looking plans. We were delighted to find a reinvigorated interest in cell and gene therapies at the conference, demonstrating a shared vision among the HIV research community for an effective therapeutic HIV vaccine.

One presentation worthy of discussion came from Sangamo Biosciences Inc. on preliminary clinical data from its Phase 1 trial for autologous infusion of CD4 cells that have undergone zinc finger nuclease mediated CCR5 disruption will confer resistance to R5 tropic virus.  The study attempts to replicate the results seen in the “Berlin Patient” who received a stem cell transplant to treat a severe case of leukemia with a donor who had a CCR5 delta-32 mutation, which prevents CD4 cells from developing a receptor called CCR5 on their surfaces, which in turn confers HIV resistance. The stem cell transplant in the Berlin Patient was successful, and nearly three and a half years later the patient remains without evidence of HIV in the circulation without the use of antiretroviral therapy. Many clinicians recognize that the “Berlin Patient” represents a success story as a “functional cure” for HIV.

VIRxSYS applauds Sangamo for its efforts to advance the progress toward an effective therapeutic HIV vaccine. However, it is premature to declare success of Sangamo’s small, early-stage study of an experimental therapy on only a handful of patients. Jay Lalezari, who presented the data at CROI, acknowledged that the engraftment seen in the Sangamo trial was far less than that seen in the “Berlin Patient.” The CCR5 disrupted cells accounted for one to six percent of the peripheral blood in five of the six patients. For complete resistance to HIV infection, one would need 100% of CD4 cells to be CCR5 disrupted, as seen in the “Berlin Patient.”

We believe that the unique approach of VRX1273 continues to show the most promise for durable suppression of viral load in infected subjects plus possible reduction of latent viral reservoirs, thus effecting a potential “functional cure” for HIV. Our preclinical nonhuman studies indicate the vaccine’s ability to fully control and suppress viral replication for as long as one and a half years post-challenge with a highly pathogenic simian immunodeficiency virus (SIV) and maintenance of CD4 counts with respect  to pre-challenge baseline values.  The simian version of VIRxSYS’vaccine was safely and repeatedly administered and proved to be highly immunogenic with sustained immune responses. We are confident VRX1273 will continue to demonstrate positive results as we move into human studies and will lead to a less-expensive, non-toxic treatment for HIV positive individuals.
http://www.virxsys.com/blog/2011/03/exploring-hiv-gene-therapy-at-croi-2011/


Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: ppp333 on March 11, 2011, 08:00:56 am
HEllo,

I don't understand how VRX1273 is intertwined with Sangamo's Zinc Finger therapy.  They seem to be two totally different methods of a "functional cure." And happy they are being considered as options dont get me wrong.

Sangamo is already working on Phase II as you can see on Quest Clinical's site.  I believe Dr. Lalezari has recruited everyone already although it is still up there...I emailed and he said we have finished recruiting for this trial.

http://www.questclinical.com/csgenehiv.html

Does anyone know what the difference of this trial will be?  Are they moving to stem cells yet?  Also Does anyone know when Paula Cannon will do the ZFN on autologous stem cells with the leukemia patients at City of Hope? When do you think results will be reported of Phase 2, at next year's CROI?, and I am sure they are following up with Phase 1 fo rmore data.  Like Jay said in the video posted on POZ fingers crossed!  I would just be concerned that if you don't have some conditioning the virus would mutate to CRX4 or become dual tropic if you only add ZFN CCR5, but like others said its possible those CD4s resistant to the virus would be able to fight it off before they can mutate...one can dream right!?

I am just grateful that things are happening...!!!!! In all aspects of this field. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on March 11, 2011, 11:48:27 am
The two approaches to functional cures aren't intertwined except that they are competitors in the race to the cure.

Dr. Lalezari's new trial is for treatment-naive individuals.  The previous trials were for people already on HAART. 

It is thought -- though far from certain -- that the modified cells will do better in individuals NOT on HAART.  The theory is that HIV will contribute to the destruction of the infectable cells, leaving a better environment for the non-infectable cells to expand.  Hopefully this trial will tell us that.   

I also think (not sure) there were some ethical concerns with asking people to go off HAART to try the gene therapy.  If a patient's medications are working and side effects are tolerable, why go off meds to try this when complications such as resistance could develop?  Obviously there is not this conflict with treatment-naive individuals.

Dr. June was asked the question re: HIV switching from R5 to X4 because of the gene treatment during the Q&A after his presentation at CROI.  He seems to think that the likelhood of this was small -- saying it took a lot of "evolutionary pressure" for HIV to do that.  It's the 4th question in the Q&A -- see link at 1:57:07

http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20445&&dp=player.jsp&e=13748&mediaType=podiumVideo

And, oh so tantalizing, is the slide at 1:51:41 where two individuals (kudos to them) did a vountary treatment interruption for 12 weeks.  The virus came back and then...it started to fall...and then ...they went back on meds.  Was this decrease part of the body's returning to a "set point"?  Random chance? Or was it the result of the modified, uninfectable cells?  This is what the next trial with the treatment-naive folks should tell us. 

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: ppp333 on March 13, 2011, 09:18:49 pm
AWESOME! Do we know when Phase 2 will begin and when we can expect results...Also is there any chance that the individuals in Phase1 will have a fucntional cure or will more results be revealed on their VL and CD4.  I know it says they will be studied for life but when should more results be discussed? Vienna?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on March 17, 2011, 02:42:26 pm
"Richmond-based Sangamo BioSciences Inc. has learned a cell therapy that is really understood to be a fantastic HIV functional cure. This will be presented as such at an upcoming AIDS conference. HIV functional cure states that somewhere between 7,000 and 8,000 prescriptions for this are being written each week since the drug was released. Doctors are still suspicious to prescribe it since it has side effects. One such side effect is kidney hurt. Nevertheless, these are some of the major researches that have taken place to find out HIV cure, and the progress is now visible."



http://best-article-directory.info/hiv-functional-cure-may-take-a-giant-leap-forward-through-hiv-zinc-finger-nucleases-that-disable-ccr5-gene/


Huh? Is this bogus or the real deal? ... The company has yet to even get to phase 2 or 3 yet, but docs are starting to prescribe this already? How so? Or am I reading this wrong?

Has anyone heard any new developments yet?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: simpleguy on March 17, 2011, 03:14:44 pm
It seems anyone can submit their own work/articles on the website you're referring. The guy probably got burned on some Sangamo stocks ... :-\
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on March 17, 2011, 03:27:15 pm
It seems anyone can submit their own work/articles on the website you're referring. The guy probably got burned on some Sangamo stocks ... :-\
I knew it was bogus....It seemed very fishy to me.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on April 12, 2011, 02:21:03 pm
This is a recent radio interview with the Alan Trounson, President of CIRM (CA Institute of Regenerative Medicine).  About 1/2 way through he talks about optimistically curing HIV/AIDS.  (CIRM is the state-funded $3 billion stem-cell organization passed by CA voters.  They are funding the Sanagamo / USC / Cannon work.  He doesn't mention Sangamo by name).

Anyway, it made my day!  It's a little dry in the beginning..very exciting in the middle!

http://blogs.abc.net.au/nsw/2011/04/a-cure-for-hiv-possibly-according-to-leading-stem-cell-researcher.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on May 10, 2011, 02:35:55 pm
Just finished listening to webcast of Ed Lamphier, CEO of Sangamo.  He was updating people on progress at the company.  Not much new to report -- some of the highlights before it leaves my brain --

Preliminary data will be released on the viremic populations (not on HAART or viremic even with HAART) by the end of the year.

They've raised $50 million -- one of the purposes was to push ahead with the HIV work.

Also, one thing I didn't get earlier from CROI but I get now.  From one infusion, about 6-8% of the T-Cells in the blood were shown to be without the CCR5 receptor.  But in the gut mucosa, where HIV is strongly present, that number approaches 100% -- what he called "selective expansion" in the presence of HIV.  Hopefully this will give us good results when the data for the viremic population is released later this year.

Finally, in the Q&A, the questioner said something like "T-Cells die out...will you have to reinfuse?" Mr. Lamphier said that, with other treatments of this type, retreatment commonly happens in the 12-24 month time frame.  The decision about reinfusion timeframes will be "data driven", he said.

He also mentioned Paula Cannon's work -- the humanized mice who received the modified stem cells (instead of T-Cells) cleared the virus in 12 weeks.  This has been reported before, but it warrants re-emphasizing. Stem cells differentiate into all types of immune cells and are permanent. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on May 10, 2011, 07:43:52 pm
Thanks for the update ;)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: newt on May 10, 2011, 07:53:16 pm
i-Base did a good write-up of the CROI zink finger/ccr5 gene research, a lay summary and more technical report.

http://i-base.info/home/croi-news-gene-treatment-boosts-cd4s

I was most taken with the CD4:CD8 ratio normalisation seen in some test subjects.


- matt
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on July 11, 2011, 11:46:20 am
The NIH is putting money into research with Sangamo and others.  (Not sure where to put this post).

Merck, Sangamo to Gain From $70 Million Boost in AIDS Cure Hunt

Merck & Co., Sangamo Biosciences Inc. (SGMO) and researchers searching for an AIDS cure will benefit from grants worth more than $70 million as the U.S. government strives for an end to the world’s deadliest infectious disease.

The National Institutes of Health awarded more than $14 million a year for five years to three groups of scientists to advance research aimed at curing AIDS, the Bethesda, Maryland- based agency said in a statement on its website today.

The biggest grant, of $6.3 million in the first year, will go to a group of 19 laboratories led by David Margolis, a professor of medicine at the University of North Carolina in Chapel Hill. He’s working with Merck to develop a line of drugs aimed at purging HIV from cells where it hides out, evading AIDS treatments and condemning patients to a lifetime of popping pills.

“The NIH has said for a while that it’s one of the top three priorities in AIDS research,” Margolis said in a telephone interview. “Now they’re putting their money where their mouth is.”

About 2.6 million people became infected with HIV in 2009, and more than 1.8 million people died with AIDS-related causes, according to the Joint United Nations Programme on HIV/AIDS.

The NIH awarded $4.2 million to scientists led by Steven Deeks at the University of California, San Francisco, who are also working with Merck, and $4.1 million to researchers led by Keith Jerome at the Fred Hutchison Cancer Research Center in Seattle, who are working with Richmond, California-based Sangamo.

To contact the reporter on this story: Simeon Bennett in Singapore at sbennett9@bloomberg.net

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net

http://www.bloomberg.com/news/2011-07-11/merck-sangamo-to-gain-from-70-million-boost-in-aids-cure-hunt.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Gio on July 11, 2011, 12:13:42 pm
Here's hoping that more funds will be forth coming..   :) 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on July 28, 2011, 07:15:02 am
"I am therefore pleased to announce today that we plans present additional data from all those in cohorts of the subjects in our SB-728-902 trial at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy or ICAAC, which will be held in Chicago from September 17thto the 20th this year. We also plan to present preliminary data from our SB-728-1002 trial at another scientific meeting later this year. We look forward to keeping you updated on this exciting and important program."

http://seekingalpha.com/article/282468-sangamo-biosciences-ceo-discusses-q2-2011-results-earnings-call-transcript?source=yahoo
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on July 28, 2011, 01:12:21 pm
SB-728-902 is for 2 aviremic groups -- on HAART and undetectable or on HAART but detectable/drug resistant.  I think this presentation will be similar to the presentation at CROI in February, only with more data.  Are the modified cells traveling, engrafting, persisting, multiplying?  That's what we would want to see here.  Not much effect on VL because both groups are on HAART.  This is coming in September.

SB-728-1002 is the big kahuna.  This trial is for people who have stopped taking meds or never started.  The modified cells should do better here -- HIV is clobbering the infectable cells, the non-infectable cells remain, multiply, and start taking on HIV itself.   If VL starts coming down without meds -- this is a real game changer.  It would main that modified T-cell infusions (or modified stem cells, even better) could lead to a functional cure.  This data will be coming late this year.  Can't wait!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on August 02, 2011, 02:13:02 pm

SB-728-1002 is the big kahuna.  This trial is for people who have stopped taking meds or never started.  The modified cells should do better here -- HIV is clobbering the infectable cells, the non-infectable cells remain, multiply, and start taking on HIV itself.   If VL starts coming down without meds -- this is a real game changer.  It would main that modified T-cell infusions (or modified stem cells, even better) could lead to a functional cure.  This data will be coming late this year.  Can't wait!

No doubt it's the big kahuna.  Sangamo and modification of T and Stem cells via Zinc Fingers has produced a lot of banter around here for a long time.  It will be good to hear if all the positive glimmers are panning out.  I think chances are it's going to be a positive deal.  Just how positive is going to take someone with a lot more scientific smarts than me to venture a guess.  Maybe Newt.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Mycen on August 03, 2011, 11:28:39 am
Hi, not sure if this has already been posted in regards to ZFP's, but I found a lecture on youtube in regards to them.  Its a series of 6 videos and is very informative on the model used to test hiv treatments on (the altered mice, which is something profound), as well as how the ZFP's play a roll, and then finally the 2 trials on T-cells and the upcoming trial on Stem cells.  The presenter is very charismatic and easy to understand (at least, I thought so).  Hope I'm posting this right as I'm new to the forums and only a month into being positive.   :P  And just trying to be positive about being positive, haha.

The author is Programforwellness, and seems fairly new seeing how many subscribers they have...
http://www.youtube.com/user/ProgramforWellness (http://www.youtube.com/user/ProgramforWellness)
There are a series of 6 clips of the lecture.  Her name is Paula Cannon, Phd. Associate Professor at U of SoCal.

Though getting hiv has sucked big time when I'm 26, I find it quite fortunate that there is such strong push right now for a cure.  Even if it doesn't fix it completely, at least progress is being made  :)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on August 03, 2011, 03:25:19 pm
Hi, not sure if this has already been posted in regards to ZFP's, but I found a lecture on youtube in regards to them.  Its a series of 6 videos and is very informative on the model used to test hiv treatments on (the altered mice, which is something profound), as well as how the ZFP's play a roll, and then finally the 2 trials on T-cells and the upcoming trial on Stem cells.  The presenter is very charismatic and easy to understand (at least, I thought so).  Hope I'm posting this right as I'm new to the forums and only a month into being positive.   :P  And just trying to be positive about being positive, haha.

The author is Programforwellness, and seems fairly new seeing how many subscribers they have...
http://www.youtube.com/user/ProgramforWellness (http://www.youtube.com/user/ProgramforWellness)
There are a series of 6 clips of the lecture.  Her name is Paula Cannon, Phd. Associate Professor at U of SoCal.

Though getting hiv has sucked big time when I'm 26, I find it quite fortunate that there is such strong push right now for a cure.  Even if it doesn't fix it completely, at least progress is being made  :)


Great, great find.  Dr. Cannon has been discussed before on these boards and is a fine spokesperson for Zinc Fingers and their potential to fight / beat the crap out of HIV. 

Thanks for tracking this down.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on August 03, 2011, 08:01:59 pm
Paula Cannon, gotta love her. Thanks for the links.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on August 09, 2011, 07:12:51 pm
Thought this was interesting.  Despite misleading headline, good news for us I think.

http://the-scientist.com/2011/08/07/when-zinc-fingers-miss-the-mark/

When Zinc Fingers Miss the Mark
Two new techniques identify how often zinc fingers nucleases cleave off-target sites.

By Tia Ghose | August 7, 2011

Zinc finger nucleases are designed to be like heat-seeking missiles, precisely targeted to find and cut specific sequences of DNA. Occasionally, however, they may snip the wrong spot, causing unintended breaks. Two papers published today (August 7) in Nature journals describe ways to systematically find such off-target action, which could one day help design gene therapies that avoid collateral damage.

“Until this time there hasn’t been a really comprehensive way of defining zinc finger nuclease specificity,” said Carlos Barbas, a chemical biologist at the Scripps Research Institute in La Jolla, Calif., who was not involved in the study. “As we begin to treat patients with zinc finger nucleases and modify genomes, we need to know where those modifications are being made.”

Zinc fingers, so named because their structure resembles a hand with a pointed finger, bind to different three-letter nucleotide sequences. By stringing together several zinc fingers and adding a DNA-cleaving nuclease, researchers can precisely target specific genes to be cut. Such specificity raises the possibility of developing zinc finger nuclease (ZFN) gene therapies. Indeed, Sangamo Biosciences, a pharmaceutical company, is testing an HIV-treatment candidate in human safety trials which uses a ZFN to modify the CCR-5 T-cell receptor that HIV uses to enter a cell.

But it’s not a perfect system: sometimes the molecule may bind and clip a different, nearly identical DNA sequence, potentially killing cells.

To systematically characterize those off-target cleavage sites, Harvard chemical biologist David Liu and his colleagues tested two ZFNs against a library of 100 billion snippets of DNA, some of which appear in the human genome. Most often, the nucleases cleaved the target site. But they occasionally cut other similar sequences as well—including one gene associated with a cancer signaling pathway.

“A superficial interpretation of our paper might lead one to be pessimistic about zinc finger nucleases, but actually I’m optimistic,” Liu said. In addition to confirming that the fraction of off-target breaks decreased with lower concentrations of ZFNs, the researchers found that using ZFNs that bind less avidly to the target sequence seemed to have fewer unintentional breaks, he said. That suggests it may be possible to design ZFN therapies in a way that minimizes those off-target effects. The researchers published their results in Nature Methods.

In the second study, published in Nature Biotechnology, researchers dosed human leukemia cells with a ZFN which cuts the CCR-5 receptor. They identified the cut locations by transfecting the cells with tagged virus particles that bound to the broken ends of the DNA, and found that by and large, the ZFN bound to the target CCR-5 DNA. About 1 in 20,000 times, however, it cleaved a second receptor gene nearly identical in sequence, as well as a few other similar sequences even more rarely. But the researchers used an extremely high concentration of ZFN, and used a cell line that is very permissive of ZFN action, to see what the worst case scenario would be, said coauthor Phillip Gregory, chief scientific officer of Sangamo BioSciences. The low rate of off-target cutting even under these conditions “validates our expectations that the proteins would be tremendously specific,” and suggests that much lower medical doses applied in the clinic would almost never be expected to cause off-target cuts, he said.

The methods might one day be used in early drug development to pick candidates with the best specificity, Barbas said. It’s unclear, however, just how comprehensive the new ZFN tests are, he said. The tagged virus particle method, for example, may miss some off-target cleavage, because the viral tags may not bind to every single break. Furthermore, Barbas added, unlike DNA in a test tube, cellular DNA is tightly wound into chromatin, so many of the binding sites found by the test tube method might be shielded from ZFNs and never be cut in living cells.

So while the new tests may be key tools for early drug development, a complete picture will only come once a person’s entire genome sequence can be had for $1000, he said, when researchers can test people who receive ZFN treatments for every off-target break.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on August 09, 2011, 08:21:13 pm
It's definitely useful information which should help come up with a more precise methodology.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on August 17, 2011, 04:26:55 pm
http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=2789&sKey=553b562f-106a-48ff-b263-3cf82d20946e&cKey=5ec79ca6-e88e-41ef-b527-7507fa2d9b91&mKey=%7B0C918954-D607-46A7-8073-44F4B537A439%7D

I don't know if this was posted yet, but the title for the upcoming presentation by Sangamo Biosciences on September 18, 2011 reads as:

"HAART Treatment Interruption following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-cells (SB-728-T) to HIV-infected Subjects Demonstrates Durable Engraftment and Suppression of Viral Load"


This "sounds" like it could be huge news, and a major, major breakthrough in the field of HIV/AIDS, but we will have to wait for the presentation itself before we make any assumptions of course.

We are about one month away. Hopefully great results will be presented.  ;)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Gio on August 17, 2011, 05:02:31 pm
AWESOME AWESOME :)  Fingers crossed  ::)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on August 17, 2011, 08:35:05 pm
I'lll have to mark my calendar.  While I don't expect this to be a pancea (I'd gladly be wrong about that though) I do find the science to be rather facinating.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Mycen on August 17, 2011, 09:31:13 pm
I am likewise fascinated by this, however I'm always optimistic.   :)  This could be it, you never know.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on August 18, 2011, 11:52:58 am
A "sneak peak" at some more VERY encouraging details that will be presented a month from now...




http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=2789&sKey=d4df5ac5-0855-47ac-9c87-f2c16aaeb7a9&cKey=72e47ff3-2053-458c-8d9c-3d32c27184a9&mKey=%7B0C918954-D607-46A7-8073-44F4B537A439%7D

Session: 042-New Therapies for HIV and HCV

Saturday, Sep 17, 2011, 4:00 PM - 6:30 PM

Presentation Title: H1-375 - Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-Cells to Aviremic HIV-Infected Subjects with Suboptimal CD4 Counts

Location: W179

Presentation Number: H1-375

Pres. Time: Saturday, Sep 17, 2011, 5:30 PM - 5:45 PM

Category: H2

Keywords: CCR5 ; HIV-therapy 

Author(s): R. Mitsuyasu, MD - Professor of Medicine1, J. Lalezari, MD - Director 2, S. Deeks, MD - Professor of Medicine 3, W. W. Tang, MD - VP, Clinical Research 4, S. Wang, MD - Director, Clinical Research 4, G. Lee, PhD - Research Scientist 4, M. Giedlin, PhD - Vice President 4, M. Holmes, PhD - Senior Director 4, P. Gregory, PhD - Chief Scientific Officer 4, D. Ando, MD - Chief Medical Officer 4;
1David Geffen Sch. of Med. at UCLA, Los Angeles, CA, 2Quest Clinical Res., San Francisco, CA, 3UCSF Sch. of Med., San Francisco, CA, 4Sangamo Bioscience Inc., Richmond, CA.

Financial Disclosures:  R. Mitsuyasu,
Sangamo Biosciences Inc Role(s): Investigator, Other, Received: Research Support.
Janssen Role(s): Investigator, Received: Research Support.
J. Lalezari,
Sangamo Biosciences Inc Role(s): Investigator, Received: Research Support.
S. Deeks,
Sangamo Biosciences Inc Role(s): Investigator, Received: Research Support.
W. W. Tang,
Sangamo Bioscience Role(s): Employee, Received: Salary.
S. Wang,
Sangamo Biosciences Inc Role(s): Employee, Received: Salary.
G. Lee,
Sangamo Biosciences Role(s): Employee, Received: Salary.
M. Giedlin,
Sangamo Biosciences Role(s): Employee, Received: Salary.
M. Holmes,
Sangamo Biosciences Role(s): Employee, Received: Salary.
P. Gregory,
Sangamo Bioscience Role(s): Employee, Received: Salary.
D. Ando,
Sangamo Bioscience Role(s): Employee, Received: Salary.

Abstract: Background: Immune reconstitution remains an issue for aviremic HIV patients who, despite HAART, have low CD4 counts. We have previously reported preliminary data on the sustained adoptive transfer of SB-728-T to aviremic HIV subjects. We report completion of enrollment of this Phase 1 study and data relating to safety, increases in CD4 cells, SB-728-T persistence and homing to gut mucosa. Methods: Nine aviremic HIV+ subjects with CD4 counts between 200-500 cells/mm3 were enrolled into 3 cohorts that received 10, 20 and 30 billion total cells, respectively. SB-728-T was manufactured with a mean CCR5 modification of 25+6%. After reinfusion, subjects were followed weekly for 1 mo and then monthly for 11 mos. Results: The median duration of follow-up for all subjects is 218 days (22-366). Data (mean+SD) through Day 28 are available on the first 8 subjects. SB-728-T infusion was well tolerated with only mild reversible infusion related AEs. Peripheral blood CD4 cell counts increased by 216+192 cells/mm3 at D28 (range -19 to 617) with restoration of normal CD4/CD8 ratios in 4 of the 7 subjects with abnormal baseline ratios. SB-728-T as measured by nested PCR ranged from 0.2 to 2.8% of PB CD4 cells at D28 and persisted for the duration of follow-up. SB-728-T was detected in the rectal mucosa of the first 6 subjects at D14 and constituted up to 6% of total mucosal CD4 cells at D90. Conclusions: SB-728-T infusion in HIV infected subjects is well tolerated. Sustained increases in CD4 cells were seen in all subjects. SB-728-T was detected at frequencies up to 5.5-fold higher than predicted suggesting expansion of these cells. The level of gene marking is approximately 1-log greater than in previous CD4 T cell adoptive transfer studies. SB-728-T distributes normally to the gut mucosa and increased over time. These preliminary data suggest that SB-728-T offers the potential to reconstitute the immune system in HIV patients.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Coolio_7 on August 18, 2011, 06:02:09 pm
The results look promising thus far. Can't wait for the presentation when more data becomes available.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on August 18, 2011, 08:51:57 pm
Hmmm.... that title ...

"HAART Treatment Interruption following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-cells (SB-728-T) to HIV-infected Subjects Demonstrates Durable Engraftment and Suppression of Viral Load"

... is very interesting.  I listened to the Sangamo investor call yesterday, and their CEO said there would be two presentations at the September ICAAC conference, one on the CROI data (presented in February) and then a second "late breaker" presentation.  This the "late breaker" session.  (He went on to say they would be presenting data from the viremic cohorts in the 4th quarter of this year.)

In the CROI data, they showed the data from the 2 patients who did a voluntary STI.  Viral rebound was delayed, then it went up, and then it declined and then....they went back on meds.  Words like "interesting" were used to describe the decline but I'm sure the word "suppression" was never used.  This title signals (to me) that they are feeling more confident re: their results.  Awsum!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on August 19, 2011, 08:23:31 pm
Hmmm.... that title ...

"HAART Treatment Interruption following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-cells (SB-728-T) to HIV-infected Subjects Demonstrates Durable Engraftment and Suppression of Viral Load"

... is very interesting.  I listened to the Sangamo investor call yesterday, and their CEO said there would be two presentations at the September ICAAC conference, one on the CROI data (presented in February) and then a second "late breaker" presentation.  This the "late breaker" session.  (He went on to say they would be presenting data from the viremic cohorts in the 4th quarter of this year.)

In the CROI data, they showed the data from the 2 patients who did a voluntary STI.  Viral rebound was delayed, then it went up, and then it declined and then....they went back on meds.  Words like "interesting" were used to describe the decline but I'm sure the word "suppression" was never used.  This title signals (to me) that they are feeling more confident re: their results.  Awsum!


Link to where I can listen to the call?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on August 20, 2011, 01:55:08 pm
Here's the link ...

http://wsw.com/webcast/wedbush17/sgmo/
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on August 25, 2011, 05:14:02 pm
Good article on aidsmap.com today about this.  Patient who had the therapy discusses his experience and his results.

http://www.aidsmap.com/HIV-gene-therapy/page/1793127/
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hellraiser on August 25, 2011, 06:00:30 pm
Good article on aidsmap.com today about this.  Patient who had the therapy discusses his experience and his results.

http://www.aidsmap.com/HIV-gene-therapy/page/1793127/

This is a fantastic read.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Gio on August 25, 2011, 09:55:12 pm
That was definitely a good article a first person point of view...  I am so impressed by his persevearance and positive outlook.. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on August 28, 2011, 08:37:18 pm
They recently updated the trial for these two studies:

http://clinicaltrials.gov/ct2/show/NCT01252641

http://clinicaltrials.gov/ct2/show/NCT01044654


A 5th cohort group was added to their NCT01252641 study (the first link) and now will be enrolling a total of 30 patients, (before it was 14).

The failed HAART group has enlarged and they are studying the Zinc Finger drug more with this group, maybe because the results are good? (This could also be great news, but again, I'm taking a wild stab in the dark)

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 02, 2011, 11:29:03 am
This is an investment analyst's rather breathless story re: Sangamo.  Should be interesting news one way or another in 3 weeks at the ICAAC.

http://seekingalpha.com/article/291210-sangamo-s-late-breaking-game-changing-news-at-icaac
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 08, 2011, 07:09:51 pm
Here's Sangamo's announcement re: what their presenting at the upcoming ICAAC conference.

http://investor.sangamo.com/releasedetail.cfm?ReleaseID=603962

Sangamo BioSciences Announces New SB-728-T HIV/AIDS Data to be Presented at 51st ICAAC

RICHMOND, Calif., Sept. 8, 2011 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that data from all dosing cohorts of its Phase 1 study (SB-728-902) to evaluate SB-728-T for HIV/AIDS as well as preliminary data from the Phase 1 clinical study of the same drug, ongoing at the University of Pennsylvania, will be presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).  The meeting will be held September 17-20, 2011 in Chicago. The abstracts will be available on the ICAAC website at www.icaac.org.

Details of the presentation follow: 
 
Abst.# H1-375: "Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-Cells to Aviremic HIV-Infected Subjects with Suboptimal CD4 Counts"
 
Oral Session: New Therapies for HIV and HCV, 4:00 — 6:30 p.m. CT, Saturday, September 17, 2011.
 
Presenter: R. Mitsuyasu, M.D., Professor of Medicine, David Geffen School of Medicine at UCLA.
 

 
Abst.# H2-794a: "HAART Treatment Interruption following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-cells (SB-728-T) to HIV-infected Subjects Demonstrates Durable Engraftment and Suppression of Viral Load"
 
Late-Breaker Poster Session: Antiretroviral Therapy of HIV-1 Infection, 11:15 a.m. — 1:15 p.m. CT, Sunday, September 18, 2011. 
 
Presenters: Dale Ando, M.D., Vice President, Therapeutic Development and CMO and Geoffrey Nichol, M.B., Ch.B., Executive Vice President Research and Development, Sangamo BioSciences, Inc.
 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 08, 2011, 07:26:17 pm
"HAART Treatment Interruption following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-cells (SB-728-T) to HIV-infected Subjects Demonstrates Durable Engraftment and Suppression of Viral Load"

<<<<<<WOW
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Gio on September 08, 2011, 08:09:35 pm
Awesome....  Definitely on my calendar to look out for
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 12, 2011, 02:15:28 am
OK, I know I'm obsessing...can't help myself :)

The Saturday presentation will be the presentation of the CROI data for the 9 patients who did not undergo a structured treatment interruption (STI).  The Sunday presentation will be a presentation of those who *did* undergo the STI.  This is the "late breaker" potentially universe-changing presentation.  There is an embargo on data for these late breakers, a condition of presenting at the ICAAC conference.  Coordinated with the late breaker presentation will be a press release from Sangamo re: the results on Sunday, Sept 18.  Then the CEO, Ed Lanphier will be speaking at two other conferences within 10 days of ICAAC.  Hmmmm....must have a story he wants to tell....

Also *very* interesting is Mr. Lanphier's response to a question regarding the durability of the treatment on a recent investor call.  Mr. Lanphier says that he believes that it may be years before the potential need for re-treatment.   In other words he believes you get a shot(s) of this stuff and you can go for years without meds.  Uh, wow.  Here's the link to the call -- it's at the end during the Q&A:

http://www.veracast.com/stifel/healthcare2011/main/player.cfm?eventName=2135_sangam
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: LM on September 12, 2011, 11:44:57 am
geobee, that's excellent, keep those news coming.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sfpvguy41 on September 12, 2011, 04:52:46 pm
the link doesn't work - i think you need an account to access the call. But that's great news.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 12, 2011, 07:14:27 pm
Yeah, I had to sign up to see the article.

Here's another article from today, less enthusiastic, but still positive.  Here are the first two paragraphs --

http://blogs.nature.com/news/2011/09/promising_signs_emerging_from_1.html

Promising signs emerging from HIV gene therapy trials - September 12, 2011

Results continue to trickle out from two clinical studies of an innovative HIV treatment, in which a subset of patient immune cells are extracted from the blood, genetically modified to make them resistant to HIV, and injected back into the patient. Carl June, at the University of Pennsylvania School of Medicine in Philadelphia where one of the trials is being conducted, presented data from the first two years at a small meeting of experts outside of Philadelphia hosted by the Foundation for AIDS Research (amfAR).

About 9 patients had completed the trial at UPenn and at the University of California in Los Angeles without any severe adverse events. And counts of CD4+ T cells, both natural and genetically altered, have gone up in all but one patient and migrated to gut mucosa. Although he could not yet speak about levels of virus in the blood for all patients, he said that their results “suggest there’s an antiviral effect,” even when antiretroviral treatment was temporarily halted for a small number of patients.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: phildinftlaudy on September 12, 2011, 07:18:15 pm
My doctor and I discussed this today right before she zapped me with the cement butt shot.... she said it is very exciting and could potentially greatly impact the way HIV/AIDS treatment is conducted.  She said that the case of the Berlin patient has opened up a lot of new avenues for treatment and possibly a cure.

She remains optimistic that HAART as we know it will be obsolete within 5 or 6 years.

I respect her opinion.  She is an Associate Professor in the Infectious Disease Division of University of Miami - and specializes in HIV/AIDS.  She works immediately under a Chief who is very involved in some of the latest treatment studies - including the use of Truvada for PREP (?).  Anyway, it was a good discussion and helped me understand up and coming research related to treatment a lot better.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 16, 2011, 02:03:31 pm
This weekend should be interesting.  Fingers crossed.

http://www.minyanville.com/businessmarkets/articles/sangamo-biosciences-hiv-aids-edward-lanphier/9/16/2011/id/36932

http://www.youtube.com/watch?v=qpGS__Y0hL0


Title: Abstract of Sangamo presentation today at ICAAC:immune system reconstitution
Post by: sfpvguy41 on September 18, 2011, 01:03:13 am
I don't know how to put all this in quotes, it is from the ICAAC website on today's presentation at:
http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=2789&sKey=d4df5ac5-0855-47ac-9c87-f2c16aaeb7a9&cKey=72e47ff3-2053-458c-8d9c-3d32c27184a9&mKey=%7b0C918954-D607-46A7-8073-44F4B537A439%7d (http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=2789&sKey=d4df5ac5-0855-47ac-9c87-f2c16aaeb7a9&cKey=72e47ff3-2053-458c-8d9c-3d32c27184a9&mKey=%7b0C918954-D607-46A7-8073-44F4B537A439%7d)

Look at the conclusions the last sentence! More tomorrow...

Background: Immune reconstitution remains an issue for aviremic HIV patients who, despite HAART, have low CD4 counts. We have previously reported preliminary data on the sustained adoptive transfer of SB-728-T to aviremic HIV subjects. We report completion of enrollment of this Phase 1 study and data relating to safety, increases in CD4 cells, SB-728-T persistence and homing to gut mucosa. Methods: Nine aviremic HIV+ subjects with CD4 counts between 200-500 cells/mm3 were enrolled into 3 cohorts that received 10, 20 and 30 billion total cells, respectively. SB-728-T was manufactured with a mean CCR5 modification of 25+6%. After reinfusion, subjects were followed weekly for 1 mo and then monthly for 11 mos. Results: The median duration of follow-up for all subjects is 218 days (22-366). Data (mean+SD) through Day 28 are available on the first 8 subjects. SB-728-T infusion was well tolerated with only mild reversible infusion related AEs. Peripheral blood CD4 cell counts increased by 216+192 cells/mm3 at D28 (range -19 to 617) with restoration of normal CD4/CD8 ratios in 4 of the 7 subjects with abnormal baseline ratios. SB-728-T as measured by nested PCR ranged from 0.2 to 2.8% of PB CD4 cells at D28 and persisted for the duration of follow-up. SB-728-T was detected in the rectal mucosa of the first 6 subjects at D14 and constituted up to 6% of total mucosal CD4 cells at D90. Conclusions: SB-728-T infusion in HIV infected subjects is well tolerated. Sustained increases in CD4 cells were seen in all subjects. SB-728-T was detected at frequencies up to 5.5-fold higher than predicted suggesting expansion of these cells. The level of gene marking is approximately 1-log greater than in previous CD4 T cell adoptive transfer studies. SB-728-T distributes normally to the gut mucosa and increased over time. These preliminary data suggest that SB-728-T offers the potential to reconstitute the immune system in HIV patients. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mdh26 on September 18, 2011, 01:09:30 pm
http://www.prnewswire.com/news-releases/sangamo-biosciences-announces-presentation-of-groundbreaking-clinical-data-from-zfn-therapeutic-for-hivaids-at-icaac-2011-130068278.html (http://www.prnewswire.com/news-releases/sangamo-biosciences-announces-presentation-of-groundbreaking-clinical-data-from-zfn-therapeutic-for-hivaids-at-icaac-2011-130068278.html)

In an oral presentation made on Saturday, September 17th at ICAAC, data were presented from all dosing cohorts of Sangamo's Phase 1 dose escalation study (SB-728-902) in subjects on highly active antiretroviral therapy (HAART) who entered the study with CD4+ T-cells counts of <500 cells/mm3 after several years of therapy ("immunologic non-responders").  A presentation made today described data from the second cohort of a Phase 1 clinical study of the same drug, conducted at the University of Pennsylvania and Albert Einstein College of Medicine, in subjects who entered the study with CD4+ T-cell counts of  >450 cells/mm3 and underwent a treatment interruption (TI) of HAART following treatment with SB-728-T.
Data from these presentations demonstrate:

- A statistically significant relationship (p<0.05) between suppression of HIV viral load (VL) and calculated levels of circulating CD4+ T-cells that have undergone biallelic modification (i.e. modification of both copies) of the CCR5 gene in SB-728-T-treated individuals who underwent a TI. CCR5 is the major co-receptor used by HIV to infect cells of the immune system.

- The VL of one SB-728-T treated-subject decreased to undetectable levels during a TI. This subject was found to be heterozygous for the CCR5 delta-32 gene mutation, i.e. half that subject's CCR5 genes were naturally disrupted. 

- Confirmation and extension of previous observations of unprecedented improvements in overall CD4+ T-cell counts and CD4+ : CD8+ T-cell ratios, as well as engraftment, expansion, trafficking and persistence of the ZFN modified cells.

- SB-728-T treatment continues to be safe and well tolerated.

"We are very encouraged by both this early demonstration of an antiviral effect of SB-728-T as well as the marked improvement in the overall CD4+ T-cell counts in treated subjects in the SB-728-902 trial," said Ronald Mitsuyasu, M.D., Professor of Medicine, David Geffen School of Medicine at UCLA and a principal investigator of Sangamo's SB-728-902 study.  "While their viral loads are well controlled on HAART, these subjects experienced incomplete restoration of their T-cell counts.  Improvement and preservation of the immune system is of paramount importance in HIV and those seen in this study show an improvement over that seen after several years of HAART."

"There is no other drug that has been shown to have the same dramatic effect on the immune system in this setting," stated Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "SB-728 treatment results in unprecedented improvement in immune system health as measured by increased CD4+ T-cell levels and improved CD4+: CD8+ T-cell ratios, even in subjects that entered the trial with poor CD4+ counts. Moreover, the interesting kinetics in viral load that we observed in the first few subjects that underwent a treatment interruption has been borne out and has allowed us to correlate a statistically significant effect of the rate of biallelic ZFN-modification of the CCR5 gene on viral load during treatment interruption."

"Data presented this weekend at ICAAC suggest that, with sufficiently high levels of circulating biallelically  modified cells and good engraftment, SB-728-T can provide a 'functional cure' for HIV," said Geoff Nichol, M.B., Ch.B., Sangamo's executive vice president of research and development.  "We continue to collect valuable data about the parameters essential for optimization of this novel drug candidate. Based on these data, Sangamo plans to continue to expand our clinical trials and carry out confirmatory studies in subjects who are natural heterozygotes for the CCR5 delta-32 mutation.  We will also explore other mechanisms to enhance engraftment and maximize the impact of the HIV resistant cells on viral load and the overall immune system of HIV patients. The ground-breaking clinical data that we and our collaborators are generating continue to validate our highly specific ZFN technology as a platform for development of novel therapeutic products."

Clinical Trial Data Summary
Abst.# H2-794a: "HAART Treatment Interruption following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4+ T-cells (SB-728-T) to HIV-infected Subjects Demonstrates Durable Engraftment and Suppression of Viral Load" Presenters: Dale Ando, M.D., Vice President, Therapeutic Development and CMO and Geoffrey Nichol, M.B., Ch.B., Executive Vice President, Research and Development, Sangamo BioSciences, Inc.

In a late-breaker session on Sunday, September 18, 2011 data were presented from the six subjects enrolled in cohort 2 of the Phase 1 clinical trial of SB-728-T conducted at the University Pennsylvania and Albert Einstein College of Medicine.  These subjects entered the clinical trial with CD4+ T-cell counts of >450 cells/mm3 and underwent a twelve week HAART TI four weeks after treatment with a single dose of SB-728-T.

The data demonstrate that: 

- A statistically significant relationship between VL and the calculated percentage of circulating CD4+ T-cells that have  undergone ZFN-mediated modification of both copies (biallelic) of the CCR5 gene within a cell (P= 0.0001 for VL at the end of TI, and 0.037 for area under the curve of VL over the TI period).

- A 0.8 to >2.0-log reduction in VL from peak during TI was observed in the 3 of 6 subjects with the highest estimated circulating levels of cells with biallelic modification. 

- One subject's VL decreased to undetectable levels such that the subject was considered to be aviremic at the end of the TI period.  This subject entered the study carrying the natural CCR5 delta-32 mutation on one copy of his CCR5 gene resulting in an estimated percentage of biallelically-disrupted CCR5 genes that was twice that of subjects entering the study with wild type CCR5 genes.

- Persistent engraftment of ZFN-modified T-cells, overall improvement in total CD4+ T-cell levels and CD4+:CD8+ T-cell ratios as well as normal trafficking of the cells and the safety and tolerability of the treatment.
Title: "Significant Progress Toward a 'Functional Cure' for HIV/AIDS"
Post by: sfpvguy41 on September 18, 2011, 01:10:39 pm
Here's the link to Sangamo's Press Release today:

http://finance.yahoo.com/news/Sangamo-BioSciences-Announces-prnews-1313979575.html?x=0&.v=1 (http://finance.yahoo.com/news/Sangamo-BioSciences-Announces-prnews-1313979575.html?x=0&.v=1)

I'm trying to read through it to understand as best as I can, and will post my thoughts, and I'm interested in what others make of this.  Overall it seems like great news and great progress, with the caveat that they think they are on the path to modify this procedure so it will be a functional cure....but they are not announcing that they have actually cured anyone yet.

Here's the highlight:
Quote
The data demonstrate that:


•SB-728-T is safe and well tolerated in this patient population with only mild, reversible symptoms typical of infusion reactions.
•ZFN CCR5-modified cells engrafted, expanded, and persisted for the duration of the study to date (Median of 337 days, range: 115-561).
•The modified cells trafficked to the gut mucosa, an important reservoir of active HIV infection.
•Notably, an increase in total CD4+ T-cells was observed in all subjects and a normalization of the ratio of CD4+:CD8+ T-cells, a measure of immunologic health, was observed in the majority of subjects that entered the study with a ratio below one.  These immunologic improvements were persistent over the study period. 
•These data confirmed and extended preliminary data that were previously reported from the first two dosing cohorts of the trial at the Conference on Retroviral and Opportunistic Infections (CROI) in March 2011. 
•In addition, data were presented from one subject in this trial who has undergone an extended treatment interruption one year after SB-728-T infusion and saw a VL reduction from peak during TI of >1-log, suggesting a potential antiviral effect  of the treatment.


Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mdh26 on September 18, 2011, 01:14:20 pm
The fact that the one subject who was heterogeneous for the CCR5 mutation went UD should mean that as long as they can improve the grafting procedure they should be able to accomplish the same thing in normal individuals. I think.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sfpvguy41 on September 18, 2011, 01:53:45 pm
I'm following a lot of the conversation about the implications at
http://www.investorvillage.com/smbd.asp?mb=1933&pt=m (http://www.investorvillage.com/smbd.asp?mb=1933&pt=m)

One person suggested something interesting: apparently about 10% of the population are Heterozygotes for the CCR5 mutation, meaning some of their cells are naturally mutated.  Sangamo reports that in one subject like this the VL became undetectable.  So if they could sort for this in studies they might prove the concept in this population first, while figuring out how many cells need to be manipulated (and how often) to make it work in the other 90%.

My question here is in the "Berlin patient" they transplanted marrow. Here they modify cells only but say they are "engrafting and durable"...so i wonder what that means to longevity of any treatment: would it last til these cd4s naturally die off and how long is that?

Something very exciting is they say they are restoring the ratio of cd8 to cd4 to less than 1 or a normal balance, which indicates less ongoing inflammation and activation of the immune system as I understand it, somehting that is a new and very exciting development.

Sangamo has a meeting sponsored by UBS Weds morning before the stock market opens to discuss "business strategies"...I wonder what's coming next!

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: boi2kwik4u on September 18, 2011, 03:59:53 pm
What does this mean for those virus attack CCR5 and CXCR4 ?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on September 18, 2011, 04:43:56 pm
Boi2, the Berlin patient actually had dual tropic HIV, and his stem cell transplant was successful nonetheless.   
http://ycopub.wordpress.com/lukesscienceblog/more-on-curing-hiv-cutting-edge-approaches-that-could-stop-the-virus-2/

I think the Sangamo news is really exciting.  Since the procedure has been found to be safe, I'm sure that in the next phase they will aim to infuse more modified t-cells, and include a cohort of people carrying the natural CCR5 delta-32 mutation on one copy of the CCR5 gene to see if they can achieve a functional cure in that subset of people first.  It will be interesting to see if they do more open ended treatment interruptions, and monitor t-cell counts and viral loads over a 1-2 year period. 

I notice they don't plan to partner with any companies on a Phase 2 trial, since they have a lot of cash on hand right now.  I hope they can enroll a substantial number of people in the Phase 2 trials. 

Over time, I imagine the treatment could be done in combination with a promising therapeutic vaccine that could train the modified t-cells to more effectively target HIV. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: boi2kwik4u on September 18, 2011, 08:28:41 pm
This is very exciting stuff.  Thanks for the info!   One more question, I had a tropism done, would they be able to tell if I have the natural CCR5 delta-32 mutation?  Also are these folks healthier overall with HIV aka elite controllers or is that something totally different?  Thanks!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sam66 on September 18, 2011, 11:46:31 pm

 Exciting news, thanks for the posts spvguy , mdh26

  Any indication of what the cost of treatment might be ?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 19, 2011, 12:21:39 am


  Any indication of what the cost of treatment might be ?

Wayyyy to early for that.  This isn't anywhere near ready for prime time and still has quite a few skeptics.  However I am sure cost would be similar to Dendrion's new prostate cancer drug which is similar to this theray in that they take your own cells tinker with them and then infuse them back into you.  Cost of that treatment is $93,000 for each treatment.   
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: d-boy86 on September 19, 2011, 07:13:48 am
Can someone break the findings down in layman terms for me please?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hellraiser on September 19, 2011, 03:15:48 pm
Can someone break the findings down in layman terms for me please?

"Data presented suggest that, with sufficiently high levels of circulating biallelically  modified cells and good engraftment, SB-728-T can provide a 'functional cure' for HIV,"

That's probably the statement that stuck out at me the most.  I believe at this point they were just going for a baseline efficacy and tolerance through the trial.  The next phase would be ramping up the amount and the number of patients.  Also patients with some sort of CCR5 mutation already seem to get better results.  They represent about 10% of the total population (I believe these are mostly caucasians of German descent).
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sfpvguy41 on September 19, 2011, 06:56:21 pm
Can someone break the findings down in layman terms for me please?

Can someone break the findings down in layman terms for me please?
An interesting challenge, one I will try since I've been thinking a lot about this one (but don't have a medical background, so consider this fodder for others here to improve).

Sangamo's approach is to take a certain number of CD4 cells out of your body, and genetically manipulate their genes so that the CCR5 receptor, which HIV uses to enter and destroy such cells, is blocked. Since this manipulation (which is what Sangamo's "drug" SB-728 does) is not 100% perfect in making this manipulation, it stands to reason that it is more effective in people who have 50% of their genetic code (from one parent) already locking out the CCR5.  So with them, there's less genetic code that needs to be successfully manipulated to have more cells successfully made resistant.

Then they place these CD4s back in your body.  What they've demonstrated is that at least for one year, such cells not only survive, but they also get to the gut mucosa, which is one of the places HIV is thought to hide even when you're on treatment.  So you’d want them to be there.  And there have been no major side effects.

The thought is, if you stop treatment, the newly circulating HIV will kill off the unmodified CD4 cells, leaving only the "new" "locked-out" cells, which then provide you with a reconstituted immune system which is itself immune from HIV-1 infection.  This is what happened with the "Berlin Patient" who was functionally cured by transplanting bone marrow which generated such modified cells from a naturally CCR5-resistant donor.  A functional cure means you may still have some HIV virus in your system, but it doesn’t do damage, since it cannot enter and kill HIV cells.  It is hoped it will die off since those target cells are not accessible, but I don’t know if this can be proven.  I believe the Berlin patient has stayed undetectable, so they can’t find circulating HIV.

In the trials so far, CD4 cells went up by an average of 200 (and this is for people who were on treatment), and interestingly, the ratio of CD4 to CD8s normalized to above 1, which is not true for most of us on treatment.  It’s now thought that this chronic activation of CD8s may  correlate with inflammation which is being blamed for all sorts of long-term HIV-related issues that mimic aging, but come early for us (stroke, “brain fog”, cardiovascular problems, heart attack).

Since the first round of testing showed a statistically significant correlation between the amount of modified CD4 cells circulating, and viral load, one may assume that by modifying more cells, or doing the treatment more frequently, that one can achieve a “functional cure” if the correlation holds.  I don’t know if anyone knows what this could mean for treatment:  once a year, once a decade, once a life with more cells modified??  It will take years of testing to learn this…but sooner it could present an option for people who are treatment experienced and resistant…as noted above in reply #135 by buginme2 there’s a link to a story about an HIV activist who had great results on this trial http://www.aidsmap.com/HIV-gene-therapy/page/1793127/.

To my knowledge no one has shown such successful correlation with a treatment or therapeutic vaccine that does not require daily meds, nor that has had such a great effect on the CD4:CD8 ratio.

And to put a positive editorial spin on it, they may have just “functionally cured” HIV patient #2, the fellow they call a “Heterozygote”, but no one can say that unless he stayed undetectable for years without meds…and that remains to be seen.  No bone transplants, just a treatment, that can be eventually commercialized.  It gives us some hope, which is always a good thing.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on September 19, 2011, 07:41:11 pm

And to put a positive editorial spin on it, they may have just “functionally cured” HIV patient #2, the fellow they call a “Heterozygote”, but no one can say that unless he stayed undetectable for years without meds…and that remains to be seen. 

That's an excellent rundown.

re: CCR5 mutation:

There are some people who have a genetic mutation called delta 32 which results in the deletion of the CCR5 gene. If  a person is a homozygous carrier that means they get the mutation from both parents (i.e. two copies) and they are essentially resistant to HIV-1 infection. Those who are heterozygous have one copy of the mutation and have a partial resistance.

According to wikipedia:

At least one copy of CCR5-Δ32 is found in about 10% of people of Northern Europe and in those of Northern European descent. It has been hypothesized that this allele was favored by natural selection during the Black Death. This coalescence date is contradicted by purported evidence of CCR5-Δ32 in Bronze Age samples, at levels comparable to the modern European population.[8] Smallpox may be another candidate for the high level of the mutation in the European population.

http://en.wikipedia.org/wiki/CCR5
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: LM on September 19, 2011, 09:34:49 pm
This is very, very promising. I was skeptical about its effect on viral load, but they did manage to bring one guy's VL to undetectable levels. We don't know for how long, but hey, they did it. Surely this can be much improved so it works well on everyone and it may be well on track to a functional cure. I'm more optimistic regarding this than before.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: boi2kwik4u on September 19, 2011, 10:15:17 pm
How much did the VL drop in the other patients?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sam66 on September 20, 2011, 07:41:33 am

 Surely this should be fast tracked somehow.

 
An interesting challenge, one I will try since I've been thinking a lot about this one (but don't have a medical background, so consider this fodder for others here to improve).



   A brilliant summery sfpvguy by the way
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 20, 2011, 01:22:17 pm
Some questions I've been mulling over since reading this excellent news:

The press releases say something like "if you get more of these cells, you'll have more of an effect on viral load."  That seems reasonable.  But can you make people undetectable if you get enough of the modified cells in them?  If so, is it permanent?  Or will we need retreatment?  If so, how often?

Of the 6 patients that did the STI, 3 had reductions in VL.  Why not all 6?

It's good to be hetero(zygous).  That patient went undetectable.  [WOW] Does this mean that all heterozygous people can become UD?  

If I'm one of those heterozygous people, would I put these things in my body even though I'm UD and healthy on an easy meds regimen?  

It's assumed that the heterozygous patient became UD because more of his cells were modified.  That seems like a big "if" to me.  Was there something else unique about this particular patient that allowed him to go undetectable?

Just some musings... and great summary spvguy41!  (Also, I read somewhere that Timothy Ray Brown has no virus in his blood or body.  He's had biopsies all over his body and no virus was detected.)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: leatherman on September 20, 2011, 01:31:00 pm
(Also, I read somewhere that Timothy Ray Brown has no virus in his blood or body.  He's had biopsies all over his body and no virus was detected.)
that's because his immune system was basically killed off by radiation and another immune system (with the CCR5 mutation) was put into him via several stem cell transplants; thus his HIV was not "cured" but rather "eradicated" as it was unable to continue replicating after the procedures were completed.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on September 20, 2011, 02:10:53 pm
Geobee, I think that all 6 subjects had a drop in viral load, but I think there's been some bad reporting about the results from non-scientific publications.  One of the findings was this: "A 0.8 to >2.0-log reduction in VL from peak during TI was observed in the 3 of 6 subjects with the highest estimated circulating levels of cells with biallelic modification."  This does not mean the other 3 did not have a significant drop in viral load.  I think it just means they had a smaller decline in viral load.  The 3 subjects with the most modified t-cells had substantial drops in viral load. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: LM on September 20, 2011, 02:38:03 pm
And the best results were on people whose modified cells expanded more. I mean, I don't know much, but the concept makes sense. HIV kills the normal cells, while the modified cells remain and expand. How long they would remain is the question.

that's because his immune system was basically killed off by radiation and another immune system (with the CCR5 mutation) was put into him via several stem cell transplants; thus his HIV was not "cured" but rather "eradicated" as it was unable to continue replicating after the procedures were completed.

leatherman, out of curiosity, what's your take on all this?

It would be interesting if newt could comment as well, since he knows a LOT.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: leatherman on September 20, 2011, 05:47:03 pm
leatherman, out of curiosity, what's your take on all this?
same take I have about all of these items here in the research thread - some day something will pan out.  ;)

Way back in the early early 90s, they told us the cure was "just around the corner". Somedays it looked that way too, what with all the info they were learning about HIV and all the advances in HAART that were beginning. It was an amazing and life-saving event to just move off AZT monotherapy and onto a cocktail of HIV meds - much less finally being assured it was working by having that new-fangled viral load test actually show that things were getting better instead of guessing by what your tcell count was doing. ::)

Yet here we are 20 yrs later, and the cure is still "just around the corner". LOL However, now they've learned a lot about HIV - and about how tricky HIV is. They've made HUGE strides in treatment and HUGE steps towards several things that might lead to the cure; but it all takes time. Of course, I've been taking my meds for two decades, always waiting for the next better med, and waiting for a cure to show up one day. I have to keep taking those meds, even if I am hoping for a cure, because right now those meds are the only thing that keep this nasty little bug from being the death of me. I'm afraid however that I'll still be waiting a while longer yet because nearly anything that is approaching even being a "cure" is still years away with plenty more testing, studying, and refinement to be done.

I love reading all the stuff here in the research thread, but I don't make any judgement call on which ones will pan out. Although I try to stay educated about these things, I'm no scientist and can't make any calls like that. LOL However, if I could guess which venture would turn out to be the cure, I could make a fortune buying up the right stock. :D So instead, I read, I follow the links, I study, I look for the "flaws" in the trials, I research who has backing, I try to understand the science of each possibility. And I enjoy each day I'm alive as much as I can because I know too many people who aren't here to enjoy any days because of this stupid virus/disease.

However, what I do know for sure is this - as long as someone somewhere is still looking for a cure, then I have hope that a cure really is "just around the corner". ;) With a little luck (and a lot of HAART LOL), I hope one day to be utterly amazed to have outlived my friends and my partners and to have lived long enough to be cured.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hellraiser on September 20, 2011, 05:51:51 pm
I'm a natural born pessimist and unlike most newly diagnosed I was sure 2 years ago that there was no cure in sight.  It does seem like they keep stacking up the lego pieces of discovery each week now though.  I figure it won't be long before there's something.  However, I remain cautiously optimistic.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: skeebo1969 on September 20, 2011, 05:53:10 pm

    I hate to minimize the discussion, but am I the only one who thinks of Lady Fingers when this thread heads the list of topic ?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: leatherman on September 20, 2011, 05:56:48 pm
   I hate to minimize the discussion, but am I the only one who thinks of Lady Fingers when this thread heads the list of topic ?
nope. :D I actually bought some in the store earlier today because this thread has been (subliminally) making me think of them.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: d-boy86 on September 20, 2011, 06:41:59 pm
I'm a natural born pessimist and unlike most newly diagnosed I was sure 2 years ago that there was no cure in sight.  It does seem like they keep stacking up the lego pieces of discovery each week now though.  I figure it won't be long before there's something.  However, I remain cautiously optimistic.
Same here. But at the rate their moving, I no longer worry about the "few" years that are subtracted from my previous life expectancy.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: spacebarsux on September 21, 2011, 12:29:11 am
Especially in the context of advancements in medicine it's been said more than once and I still believe it's a wise way to think:

"I am not opposed to optimism but I am fearful of the kind that comes from self-delusion."
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sam66 on September 21, 2011, 07:07:12 am

 Yep, I feel so sorry for all those deluded researchers working tirelessly towards a cure
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: spacebarsux on September 22, 2011, 06:21:11 am
<sigh> Not deluded researchers. Just saying that I prefer to be cautiously optimistic about the research so that when (please note I didn't say "if") a cure comes along, I am pleasantly surprised rather than delude myself into thinking it's gonna be available for all of us in 2015 which is a sure way to set yourself up for disappointment.

But I digress, I came here to say that I just read this:

A person with HIV who didn't take antiretroviral drugs for three months remained free of the virus, thanks to a groundbreaking gene therapy. The success raises the prospect of keeping HIV in check permanently without antiretrovirals.

The gene therapy works by locking the virus out of the CD4 white blood cells it normally infects. Of six people with HIV given the treatment, one cleared the virus completely and another two saw 10-fold drops in circulating virus.

"We're over the moon to have seen that in this small phase I study," says Jeff Nichol, executive vice president for research at Sangamo BioSciences, the company in Richmond, California, that is developing the treatment. "Having one virus-free patient and 10-fold reductions in another two is amazing."

Most importantly, analysis of data from the six patients, and from four others in a separate trial, revealed the secret of the more successful outcomes, paving the way for the therapy to work better in future.


http://www.newscientist.com/article/dn20948-double-whammy-gene-therapy-clears-hiv-from-body.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on September 22, 2011, 08:47:03 am
I wouldn't be surprised if the heads of the large pharmaceutical companies that make HIV meds (Gilead, Bristol Myers, etc) are seriously considering buying Sangamo.

This treatment could possibly be a game changer and it would eat up their profits unless they get in on it.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 22, 2011, 10:48:17 am
I wouldn't be surprised if the heads of the large pharmaceutical companies that make HIV meds (Gilead, Bristol Myers, etc) are seriously considering buying Sangamo.

This treatment could possibly be a game changer and it would eat up their profits unless they get in on it.

Maybe, however I read an article about this treatment in MIT's tech magazine and the author was Arguing how this treatment would NOT be a game changer on a global scale due to its expected cost.  Gene therapy isnt cheap (it could run close to $100,000) which would make it Impractical in the majority of the world.  They also said that Sangamo has enough money on hand to continue its clinical trials on their own without seeking money from any of the major pharmaceuticals.  Sounds like they are investing quite a bit hoping for a big payout.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: LM on September 22, 2011, 11:10:15 am
A person with HIV who didn't take antiretroviral drugs for three months remained free of the virus, thanks to a groundbreaking gene therapy. The success raises the prospect of keeping HIV in check permanently without antiretrovirals.

This is great, let's hope this guy continues virus-free.

But I also think that, even if this comes as a cure, ARVs will continue to profit, as most people won't be able to pay for such treatment.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tim Horn on September 22, 2011, 01:53:26 pm
A person with HIV who didn't take antiretroviral drugs for three months remained free of the virus, thanks to a groundbreaking gene therapy. The success raises the prospect of keeping HIV in check permanently without antiretrovirals.

The gene therapy works by locking the virus out of the CD4 white blood cells it normally infects. Of six people with HIV given the treatment, one cleared the virus completely and another two saw 10-fold drops in circulating virus.

And here we have journalism that is either lazy or irresponsible, depending on your point of view.

The "one patient" being referenced here never became "HIV free." His viral load basically remained undetectable when his antiretroviral therapy was stopped. But he was no more "HIV free" than the rest of us with undetectable viral loads. What's more, this patient wasn't your usual HIV case -- he had a natural variation in the CCR5 gene (he inherited one delta-32 mutated form of the gene from a parent) that resulted in lower CCR5 coreceptor expression on his CD4 cells and, with that, a much slower course of HIV disease progression (inheriting a mutated gene from both parents essentially blocks all production of CCR5 on CD4 cells; but this is a rare situation). So basically, the infusion of gene-modified stem cells made a good thing even better for this one particular patient.

So this guy head a head start that more than 90 percent of the rest of us shouldn't expect. But there's something to be learned here. Along with data from the study showing that those who had maintained the highest percentage of CCR5-deficient CD4 cells following infusion -- both in the blood an in the gut -- had the lowest viral loads while off treatment, these data suggest that if Sangamo can find a way to safely and economically increase the number of gene-modified CD4 cells infused back into the patient, the results may be even better in a majority of study subjects.  The Phase I study looked at infusions of 10 to 30 billion cells (approximately 1/4 of which were successfully modified); future studies may want to look at infusing an even higher number of cells and/or developing a method of increasing the percentage of CCR5-deficient cells before infusion.

Tim  
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Jake2011 on September 22, 2011, 04:26:37 pm
I wouldn't be surprised if the heads of the large pharmaceutical companies that make HIV meds (Gilead, Bristol Myers, etc) are seriously considering buying Sangamo.

The thing that worries me about this Inch is that it could actually happen, if sangamo got bought out by the big pharmies all they would then have to do is bury it, stick it in a safe and throw away the key, research stopped at phase I or II trials, no credible reason given, it's happened before! It's all about the greenback and if that’s what they have to do to protect their billion dollar industry, then surly they'll do it!?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 22, 2011, 08:58:47 pm
I agree that it's a leap to say that the undetectable patient is virus free.  But, well, do we know conclusively that he isn't? 

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: VariGam on September 22, 2011, 09:29:51 pm
The thing that worries me about this Inch is that it could actually happen, if sangamo got bought out by the big pharmies all they would then have to do is bury it, stick it in a safe and throw away the key, research stopped at phase I or II trials, no credible reason given, it's happened before! It's all about the greenback and if that’s what they have to do to protect their billion dollar industry, then surly they'll do it!?

The Sangamo CEO has specifically said that they will not be partnering for a Phase II trial.  According to their financials they do have sufficient cash available to pay for a Phase II.  If this can make it to Phase III it will be a different story.  Those are much more expensive, so I assume they would have to take on a partner.  (which would be good for the stock price! yay)

As for your point about big pharma shutting this down, simply put thats not going to happen imo.  There would be a ton of money to be made from this type of treatment.  It would be very expensive and its not like you would just go to a clinic, get one shot, then be cured.  There would likely be many many treatments throughout the course of your life.  This could be a gold mine for them as well.  Also, as someone else mentioned, many would not be able to afford this treatment so ARVs would still be profiting handsomely.

edit: I also wanted to add that this type of treatment is likely a looooong way away.  Someone in this thread mentioned 5-6 years, but reality is closer to 10-15.  They are just beginning the initial research and lots of tweaking/testing has to be done before its ready for the clinic.  However, it is very exciting research!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mdh26 on September 22, 2011, 09:30:43 pm
It makes absolutely no sense to consider the UD guy to be cured / virus free. Like none, nobody is making that claim.

And it will not last forever. It will be interesting to see how long he'll remain UD without another treatment, but until they can modify his stem cells that produce the cd4 cells, it's just a temporary treatment, even if it lasts for a year or two.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on September 22, 2011, 10:04:54 pm
And here we have journalism that is either lazy or irresponsible, depending on your point of view.


Yea, when I read that part about the patient having "cleared the virus" it was a definite red flag indicating the statement was obviously wrong. People who are not as in tune with HIV research as are those of us with HIV wouldn't bat an eye when reading such a claim.

 
The thing that worries me about this Inch is that it could actually happen, if sangamo got bought out by the big pharmies all they would then have to do is bury it, stick it in a safe and throw away the key, research stopped at phase I or II trials, no credible reason given, it's happened before! It's all about the greenback and if that’s what they have to do to protect their billion dollar industry, then surly they'll do it!?

Apart from the fact that, as others have said, Sangamo isn't planning on selling the rights to this, the fact is that even if they did partner with someone, the contracts for such rights I'm sure include protections to the effect of "if the product isn't developed and 'exploited' the rights would revert, etc."

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: John2038 on September 22, 2011, 10:26:19 pm
On the paper, this can lead to a functional cure:

1) To replicate, HIV needs the co-receptors CXCR4 and CCR5.
2) Without them, it can't replicate.
3) ZFN is able to disrupt these R5 and the X4 co-receptors in T cells
4) ZFN proof of concept has shown that there was a good uptake (grafting) of the modified CD4

I'm not trying to say that in the reality, ZFN IS a functional cure. But rather, being given the fact above, it is definitely a very interesting study that will have most probably positive outcomes.  My two cents are that ZFN will be part of our treatments options tomorrow. It would be interesting to see if ZFN can be the answer to resistances. I would be interested seeing another study blocking both co-receptors (we will then become even closer to the conditions that has lead the Berlin patient to be cured).
If only we could make the chemio much safer and find a way to transplant our own bone marrow that has been, gentically manipulated in a way that 100% of the T cells it produce are R5 free (or R5/X4 free). That would be something I guess.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: LM on September 23, 2011, 12:27:26 am
I ended up saying "virus-free" from following the article, but I meant undetectable. Of course it doesn't mean he has cleared his body from HIV.

Besides, I remember I read somewhere that if this worked, it wouldn't take 10-15 years, but less. They are on human trials already. Anyway, let's hope this works.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sam66 on September 23, 2011, 12:30:54 am

The "one patient" being referenced here never became "HIV free." His viral load basically remained undetectable when his antiretroviral therapy was stopped. But he was no more "HIV free" than the rest of us with undetectable viral loads.

 Yes, this is someting that always puzzled me, how can we ever know if someone is free of the virus or cured,  even in the case of Berlin patient until we know where all the viral reservoirs are, or until you test every organ in the body for the virus.

  Is this what is meant by a functional cure ? some one can remain UD without treatment
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sfpvguy41 on September 23, 2011, 01:10:07 am
Yes, this is someting that always puzzled me, how can we ever know if someone is free of the virus or cured,  even in the case of Berlin patient until we know where all the viral reservoirs are, or until you test every organ in the body for the virus.

  Is this what is meant by a functional cure ? some one can remain UD without treatment

As i understand it yes, that would qualify. But if there was some small amount of virus in the body, and it was controlled and didn't do damage, that would still be a functional cure. The reason we have immune systems is there are always viruses around the cd4s and other cells attack and destroy them.  We are never virus-free, just some attack in ways way more dangerous than others.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sfpvguy41 on September 23, 2011, 01:16:59 am
I agree that it's a leap to say that the undetectable patient is virus free.  But, well, do we know conclusively that he isn't? 



As I understand it, there were two cohorts in the recent Phase 1 studies.  In the first cohort, they never stopped ARV treatment. In the second, it was part of the protocol that they stop treatment for 12 weeks only, and the undetectable patient was in this group. Presumably for safety reasons, he went back on treatment so we will never know for how long he would have stayed undetectable.

We need to focus on the fact that anyone became undetectable at all was amazing, and that all had viral load drops correlated with the amount of modified CD4 cells when they went off treatment was also good news. One would expect anyone going off meds to have viral load increase, so it clearly shows proof of concept.  Onward to new trials!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on September 23, 2011, 08:38:53 am
Yes, this is someting that always puzzled me, how can we ever know if someone is free of the virus or cured,  even in the case of Berlin patient until we know where all the viral reservoirs are, or until you test every organ in the body for the virus.

  Is this what is meant by a functional cure ? some one can remain UD without treatment

Well, in the case of the Berlin patient they are doing very sophisticated tests that check virus in every nook and cranny. They might still be missing some areas but they have also found that, as time goes by, he has fewer and fewer levels of HIV-antibodies in his system so it's predicted that at some point he will actually test HIV-negative, if those antibodies disappear.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sam66 on September 23, 2011, 09:49:17 am

 they have also found that, as time goes by, he has fewer and fewer levels of HIV-antibodies in his system so it's predicted that at some point he will actually test HIV-negative, if those antibodies disappear.

 I guess that would be the litmus test, if he does eventually test hiv -ve, then we can say at least one person
has been cured,.. Amazing I hope that day comes soon for him, I will celebrate that date for him.

 Just to digress a little , I read in the news today, " The absolute truth, The universal constant " nothing
 travels faster than light may not be true.
    Scientist at CERN may have discovered a Neutrinos which can travel faster than light, if this turn out
 to be true, that would be amazing, the impossible has happened.

     http://www.bbc.co.uk/news/science-environment-15017484

  may be oneday we may have a cure for everybody........ impossible ?

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 28, 2011, 04:19:28 pm
Just listened to one of Sangamo's investor webcasts.  There are going to be two new trials in the first half of next year:

1.  Using SB 728 with a heterozygous population.  This is to try to replicate the one patient going undetectable after the 12-week STI.  (Interesting, after going back on meds, this patient blipped up to 100).

2.  Using enhanced engraftment techniques with SB 728.  Ed Lanphier (Sangamo's CEO) said that techniques can increase engraftment up to 1000 times.  (My guess here is that they will somehow suppress one's own T-Cells to give "space" for the modified T-Cells to expand.  Like I said, this is a guess here.)

The trials this year gave a clear result -- the more cells you modify, the greater the anti-viral effect.  These next two trials should result in a lot of modified cells -- and even greater control of the virus.  Cool stuff!

Here's the link.  I think you have to log-in to see it.  The slides and Q&A at the end are worth looking at.

http://wsw.com/webcast/jmp14/sgmo/
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Inchlingblue on September 28, 2011, 08:36:20 pm
Thanks for that, geobee . . . it's a good overview of what's to come.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: VariGam on October 03, 2011, 03:02:43 pm
Shouldn't more results for treatment naive patients be coming out later this year?

Also, this isn't relevant to the topic but the stock is down 26% today on news of the failure of their diabetic neuropathy therapy. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on October 04, 2011, 09:27:48 pm
Results for the treatment-naive cohort are coming out near the end of the year.

Also, they are actively screening for the heterozygote/STI trial at Quest in San Francisco (www.questclinical.com).  They took some blood to see if I qualify -- a 10% chance.  They are looking for a) undetectable on meds b) good T-Cells and c) of northern European descent (most likely to be a heterozygote).   If you're interested, their contact info is on their website.  This trial isn't yet listed on the website, but they told me today they are actively looking for more people.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: mbpoz6 on October 08, 2011, 12:52:39 pm
http://www.insidebayarea.com/news/ci_19064977

Small HIV studies show promising signs

A novel chemical editing of a gene strengthened immune systems in HIV-positive men, and one participant even cleared the virus without drugs, scientists recently announced.

"We were stunned," said Elizabeth Wolffe, a scientist with Sangamo BioSciences in Richmond, which developed the gene therapy. "It isn't usual that someone would clear their virus without having medication."

The gene therapy altered a critical class of immune cells -- T cells -- the front line in battling the virus. HIV defeats this defense by latching to T cells and destroying them.

The therapy snipped out a gene that enables the virus to attach to T cells, so they could deflect the deadly virus, study results indicate. On its own, the virus exists for less than a day, and it needs the immune cells to survive and multiply. An army of genetically altered T cells deflecting HIV would deplete the virus' ranks, one researcher said.

The altered immune cells were also replicating, buoying hopes of long-term protection.

Given the small size of the trials -- nine men in one and six in the other -- researchers tempered their responses to the early results. But scientists say they point to a promising way to clear the virus without the difficult side effects and high cost of a lifetime of antiretroviral medications, which run $15,000 to $20,000 a month. Patients in the trials had only minor and transitory side effects, Sangamo BioSciences reported.

"Do I think we have a cure?" said Dr. Pablo Tebas, a University of Pennsylvania researcher running one of the trials. "No, but I think it's a very exciting result that points in the direction we need to go. And then maybe we will one day reach that holy grail, not needing antiretroviral therapy.

Medical advances rely on repeated successful tests of a treatment with large groups of study subjects, and many questions also remain unanswered with the Sangamo trials, including how long the genetically modified cells will last.

The genetically altered T cells retain their typical behavior, racing to attack bodily invaders. During the study, the modified cells traveled where "HIV reservoirs" are known to hide out, such as in the gut, Wolffe said.

It's these hidden reservoirs that keep T cell counts low for some HIV carriers even when blood levels of the virus are undetectable, as the virus can still destroy T cells from its redoubt.

The findings were presented Sept. 17 and Sept. 18 at a Chicago medical conference.

A Brisbane man in one of the trials said his low T cell count almost doubled two weeks into it and has remained there.

For the first time in years, Matt Sharp, 55, said he hasn't picked up an upper respiratory infection, such as a cold, the flu or pneumonia. "It's phenomenal," he said.

Sharp knows he can't prove it, but he attributes his rise in T cell levels to his illness-free year.

The scientists used a type of genome manipulation that employs "zinc fingers," which are two protein strands bound by a zinc atom that resemble a finger. They precise "edit" genetic material.

For both of the studies, researchers collected T cells from the blood of each participant and with zinc fingers deleted the gene for the HIV attachment site. The patient's own genetically modified cells were then reinfused into his blood.

In the Sangamo-run trial in California, Sharp and eight others had been taking medications that had driven HIV to an undetectable level in their blood. But they still had low T cell counts -- the sign of a weakened immune system vulnerable to disease. HIV infections can lead to AIDS, the syndrome in which the weakened immune system is unable to fight off a range of serious infections.

The California study is expected to end in 2012. Sangamo BioSciences said results so far show the altered T cell infusions led to "unprecedented improvements" in all the men's T cell counts compared with prescription drugs, including antiretroviral therapy.

The six men in the University of Pennsylvania trial also were taking HIV medications that had cleared the virus from their blood but had high T cell counts -- so their immune systems were relatively strong.

They were given a 12-week "drug holiday" to test the effect of the altered cells alone.

As expected, Tebas said, their HIV blood levels spiked.

But then with infusions of their modified T cells, the HIV levels declined. One participant who carries a gene that naturally creates T cells lacking the HIV receptor even cleared the virus without help of drugs.

Tebas said the man simply had more of the modified T cells in his blood, given his natural supply and the infused T cells.

"So it clearly suggests it's a dose issue," Tebas said.

Sangamo BioSciences next plans to begin studying the effect of the modified T cells on those who are HIV-positive and also carry one of the genes for HIV resistance.

"It's promising," said Dr. Jay Levy, a UC San Francisco AIDS researcher who codiscovered HIV. "You can't say anything less than that or any more than that. But the results put forward are very encouraging."






From reading this article a few things are not that clear to me. What I don't understand is when they say one participant "cleared the virus"....does that mean its gone from his/her body due to the treatment? OR was it just not detected during the STI then returned? Or is it something else?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on October 25, 2011, 06:38:42 pm
Just a quick update -- Sangamo is dropping the current trial SB-728-1002, the treatment-naive cohort, in an effort to focus on their two new cohorts.  However, from what I can tell, there will be an update on SB-728-1002 next Tuesday. It will be discontinued in favor of the other two trials (heterozygotes and enhanced engraftment) to be begin enrolling in the first half of next year.   -- George
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on October 25, 2011, 08:09:44 pm
Yes, Geobee, there's more info on this from Sangamo's presentation at a teleconference last Friday.  There's a somewhat lengthy transcript here.

http://www.investorvillage.com/smbd.asp?mb=1933&mn=42641&pt=msg&mid=11079955
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: AlexMerida on November 07, 2011, 07:16:18 pm
can we  do something... in order to move cure-related research  forward as quickly as possible
We have to organize and give money to the researchers in order to catalyze the new promising therapies.. watch the work of abzyme form Professor Sudhir and the work of prof Loyter with the mix. They are the only one who have succeeded in controlling and eradicating HIV but they need dollars and the big pharmacy...we are the only interested. We do not have much time
As as community we need to stay involved ……
The benefits we have in our  life today  with ARV are because people took risks
I am totally new in these matters,  I jus have been diagnosed and about to start ARV,  and my friends always tell me that I am new and with time I will get used and after all I have my meds for sure that there is nothing to worried  about. But what about the rest of the world….more than halve of the polulation do not have acces to HIV drugs.
It is been 30 years but I do not think that all those year we have the conciseness about that years have passed but I do not think that we have struggled a real  battle it seem more like we are just pretending that we were fighting against HIV.
Friend always tell me that the cure will be in 20 o more and maybe it will be like cancer
Does anyone know the work of Zachary Benett for Abzyme
I contact Yissum the company who will commercialize the inventor  of Dr. Loyter and they told me that they are working on that..in fact de do not have any pharma interested.
so it is been 30 years and is time to believe. Or more accurately it is time to do real work
the  government has done ist part but what about us?
Many people are in the comfort area...but I  would ask them what can you give if you have the chance to be one day free of HIV..it  is possible but we have to catalyze it
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on November 14, 2011, 06:46:53 pm
This is about a month old, a Paula Cannon interview from NBC LA.  She speaks so knowledgably, confidently -- such an inspiration!  Not much "new" news here, but it made me feel that one day this treatment is going to work.  

Note:  Copy and paste the whole link -- don't know why it doesn't appear correctly.

http://www.nbclosangeles.com/video/#!/on-air/as-seen-on/The-Fight-Against-HIV-AIDS-Goes-On/132119743
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: TonyDewitt on December 29, 2011, 05:21:56 pm
Sangamo's clinical trial on T-cells treated with ZFP's seems very promising, and appears to be the on-ramp for Paula Cannon's work on stem cells treated with ZFP's. If she can get the government to allow a clinical trail for that, we might be looking at the end of AIDS, if not the end of HIV. Apparently the funding structure in California requires that any candidate treatment be within four years of going to clinical trials, so the pressure is certainly on to get candidate treatments into clinical trails. Someone mentioned earlier Sudhir Paul's work with Abzyme Research Foundation, again very brilliant work, worth mentioning because these two avenues seem to be the best bets for saving lives from HIV. Maybe someday in the future we will see people treated with a combination of therapies.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on December 29, 2011, 06:35:23 pm
She has shown that ZFN-treated stem cells have eliminated HIV in humanized mice.  I also think that the ZFN-treated T Cells might work.  Sangamo's currently expanded the number of recruiting sites to find heterozygotes (I got myself tested and wasn't).  The "Trenton" patient (a heterozygote) went UD (at least temporarily, I don't know the longer term data) and they are trying to replicate that.  They are also preparing another trial to encourage the uptake of treated T Cells in non-heterozygotes.  From what I've read, this second trial will require a resubmittal by Sangamo -- they can't just tack it on to their existing trial.  From what I gather it also involves suppressing one's own T-Cells to give the newly expanding cells "space".   I haven't seen any recruitment for this second trial yet but expect it will be begin in the second half of 2012.  That's just a guess, though.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on December 30, 2011, 03:05:03 pm
Your day need a lift?

Here's a quote from Alan Trounson, who directs the California Institute of Regenerative Medicine. CIRM, funded by a California state proposition, is funding Paula Cannon's work (and I think Dr. Baltimore's, but I'm not sure about that). 

This is from Stem Cells Translational Medicine, January 2012 --

"HIV research is another area where CIRM-funded scientists are making great advances -- so much so that I am convinced a cure based on stem cells will soon be discovered for this disease and that this approach may one day
result in the eradication of HIV from the world."

That's better than a poke in the eye.  Here's the link to the entire article. 

http://www.cenveomobile.com/issue/49332/15
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on January 09, 2012, 11:37:11 am
Here's today's press release about the two new trials from Sangamo.  The first (SB-728-902) is the Phase II trial of 20 heterozygotes "Cohort 5".  The second (SB-728-1101) is the Phase 1/2 trial of at least 9 patients whose T-Cells are reduced with Cytoxan.  In theory, this will give room for the newly-injected modified cells to expand and engraft. 

I was surprised to see the second trial being announced so quickly.  Sangamo had a big disappointment at the end of 2011 with a drug for diabetic neuropathy -- perhaps this has pushed them to move ahead more quickly with their efforts in HIV.  That's just speculation.

Here's the link to the PR:

http://www.prnewswire.com/news-releases/sangamo-biosciences-announces-initiation-of-two-new-phase-2-hiv-clinical-trials-136929243.html

[Appended]  Cytoxan can have serious side effects.  From Wikipedia:

"Many people taking cyclophosphamide do have serious side effects. Side-effects include chemotherapy-induced nausea and vomiting (CINV), bone marrow suppression, stomach ache, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, and lethargy. Hemorrhagic cystitis is a frequent complication, but this is prevented by adequate fluid intake and Mesna (sodium 2-mercaptoethane sulfonate). Mesna is a sulfhydryl donor and binds acrolein.
 
Cyclophosphamide is itself carcinogenic, potentially causing transitional cell carcinoma of the bladder as a long-term complication. It can lower the body's ability to fight an infection. It can cause temporary or (rarely) permanent sterility. A serious potential side-effect is Acute Myeloid Leukemia, referred to as secondary AML, due to it occurring secondarily to the primary disease being treated. The risk may be dependent on dose and a number of other factors, including the condition being treated, other agents or treatment modalities used (including radiotherapy), treatment intensity and length of treatment. For some regimens it is a very rare occurrence. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) seems to carry an AML risk of less than 1/2000th, with some studies even finding no increased risk compared to the background population. Other treatment regimens involving higher doses may carry risks of 1-2% or higher, depending on regimen. Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After 9 years, the risk has fallen to the level of the regular population. When AML occurs, it is often preceded by a Myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML."
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: surf18 on January 09, 2012, 07:53:38 pm
that sounds horrid!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on January 12, 2012, 07:09:44 pm
Yeah, it does sound horrid.  All depends though on the dosing.  In more news, here's the transcript of Sangamo's press conference today with CEO Ed Lanphier.  Not much new news, but interesting nonetheless. 

http://seekingalpha.com/article/319266-sangamo-biosciences-ceo-presents-at-the-30th-annual-j-p-morgan-healthcare-conference-transcript?source=yahoo
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Mycen on January 13, 2012, 09:28:30 am
Thanks for the update, news has been pretty dry on hiv research.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on January 13, 2012, 04:48:15 pm
I think that Sangamo has not been trumpeting the news on HIV because they got burned by the diabetic neuropathy trial last year.  But these two trials that will soon be underway are very big deals. In 2012 we will know if they can give a functional cure to heterozygotes.  If they can that is a game changer. It also means they can probably do the same for the rest of us.  Huge.

And if that doesn't work, the stem cells have a good chance of working.

Finally, when I went to the doctor to participate in a study, he said that the pharmaceutical companies are now finally interested in a cure because the drugs are coming off patent.  I think the pressure to find new profits and competition from companies like Sangamo will lead to a cure.   

Sorry for any fat fingering. On my phone.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: lmdo on January 16, 2012, 05:44:37 am
True Mycen, new promising research news has been scarce. Fingers crossed still.
 :D
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: emeraldize on January 31, 2012, 04:46:42 pm
http://www.youtube.com/watch?v=1FejpwZZfGM


Bloomberg report on Sangamo. Stock's jumping.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: contagion on January 31, 2012, 05:22:56 pm
The video says results are to be expected end of this month  - I presume Feb 2012 ? What results though?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: emeraldize on January 31, 2012, 08:56:27 pm
This adds a little more, but not the exact meetings nor dates for announcements. http://investor.sangamo.com/releasedetail.cfm?ReleaseID=637760
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on January 31, 2012, 09:10:05 pm
That video clip is about a year old, so she's talking about the phase 1 results that were going to come out in 2011.  If you look at the stock prices they showed, they are from the end of 2010.  Since then, prices have gone down, although they are creeping back up. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: emeraldize on January 31, 2012, 09:17:05 pm
CD: Thanks for pointing that out -- I'll look into it. A friend sent it to me today stating it was freshly posted. Em

http://www.youtube.com/watch?v=1FejpwZZfGM

Nope, it's current. I've reposted the same link here as in the previous post. http://www.marketwatch.com/investing/stock/sgmo
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: contagion on January 31, 2012, 10:31:34 pm
I'm excited about this trial...though they wish they had some kind of timeline. I would line up to enroll in Phase 3!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 09, 2012, 12:40:28 am
Sangamo has started dosing some of the heterozygotes.  They haven't yet started dosing for the Cytoxan trial.  At CROI they will present more data from last year's trials (not these trials). 

It's exciting that they've got the first trial underway.  In about 6 months they'll know if it works on the heterozygotes.  If those individuals get undetectable without meds, they're going to stay off meds as long as they remain UD.  (The Trenton patient in last year's trial went UD, but the trial protocol required he go back on meds anyway and he did.)

Here are the relevant paragraphs from today's earnings call.  Quoted is Geoff Nichol, the science guy at Sangamo:


"In this study, we are enrolling up to 20 delta-32 heterozygote subjects, who are on HAARP and who will undergo a 16 week treatment interruption two months after SP-728-T treatment. This study will, as previously, reinstitute HAART if a subject's CD4 counts fall below a certain threshold. Or viral loads rise too high to too high a level. But importantly, will also have the provision to delay resumption of HAART if patients are aviremic at the end of the 16 week TI period. This trial is progressing well, and we have treated our first subjects under the protocol.

The second trial that we have initiated, SP-728-1101, takes the observation of enhancing engraftment of biallelically modified cells much further and applies it to the entire population of HIV infected subjects. The rationale behind the study design is to use what is called a lymphopenic preconditioning regimen that temporarily depletes lymphocytes from the subject and not only makes space for our modified cells but sets up a response in the body that signals all lymphocytes, including the ZFN modified cells, to rapidly multiply to address this depletion.

Our newly opened SP-728-1101 clinical trial, a phase 1-2 dose escalation study. We are using Cytoxan, administered one day prior to SP-728-T infusion to transiently reduce the numbers of lymphocytes in the body which will rapidly repopulate once the drug is discontinued. This approach has been used to enhance and engraftment the reductively transferred T-cells in the treatment of cancer and has been safely used experimentally in patients with HIV and as therapy for several autoimmune diseases.

We are enrolling at least nine HIV infected subjects on HAART into three dose escalating cohorts. One day after receiving Cytoxan subjects will be infused with SB-728-T. Six weeks after that infusion subjects will undergo a 16 week TI of their antiretroviral therapy. This study will as will the Delta 32 heterozygous study reinstitute HAART if a subject CD4 count falls below a certain threshold or viral loads rise too high a level. But importantly, we'll also have the provision to delay resumption of HAART if patients are aviremic at the end of the TI period.

In addition to safety and viral load reduction, we will evaluate the effective escalating doses of Cytoxan of 728-T engraftment, the change in CD4 T-cell counts in peripheral blood, and the long-term persistence of SB-728-T. We expect to present data from these trials at appropriate scientific meetings and we'll provide more guidance as to data presentation timing as the trials progress.

However, regarding earlier Phase 1 studies, I can tell you that we will be presenting additional important follow-up data at this year's Conference for Retroviral and Opportunistic Infections or CROI, which will be held in Seattle in early March."

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 15, 2012, 11:49:22 am
Great article in Scientific American by Carl June and Bruce Levine -- well worth the read.

http://www.scientificamerican.com/article.cfm?id=blocking-hivs-attack

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on February 15, 2012, 12:40:16 pm
Really good article.  Covers some of the same ground as has been discussed here at length, but for anyone wanting perspective on this soon to be game changing technology, it's worth a read.

The last line is encouraging and says a lot:

"Even if our custom-designed zinc finger nucleases are not a cure, we believe they could be the closest anyone has come to locking out HIV in 30 years"

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Pepino2 on February 17, 2012, 06:26:36 pm
big news yesterday.  president and CEO of sangamo states the following at the leerink health investment banker presentation.  SGMO stock price pops 27%.

From IV board
]-->A: Speak first to level, del 32 heterozygote in 12-15% biallelically modified T cells. That is a signal. Can achieve in del 32. Think much higher levels in enhanced engraftment. Think works in all patients, not just heterozygotes. What drives us, viral load, end points, what is functional cure.


EL answers that he thinks that 15% modified T-cells is the signal point (think cure). He goes on to say that he thinks they can reach much higher levels than this with the enhanced engraftment trials they are currently running. If he is right, SGMO is about to produce trial results where AIDs patients stop HART, receive T-cells, and stay off of HART. Sounds like a functional cure and the people cured will be announcing.

They have to go public on this news as it is affecting stock price materially.

:)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: contagion on February 19, 2012, 02:14:50 pm
From IV board
]-->A: Speak first to level, del 32 heterozygote in 12-15% biallelically modified T cells. That is a signal. Can achieve in del 32. Think much higher levels in enhanced engraftment. Think works in all patients, not just heterozygotes. What drives us, viral load, end points, what is functional cure.

I'm not understanding much of that...but I like the keywords in your post!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 19, 2012, 07:33:33 pm
This run up in price on no "new" news making me think they might be a take over candidate. Hope big pharma doesn't buy them and put their HIV work on the back burner.  Probably just being paranoid.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 29, 2012, 11:57:01 am
Here's an article on Daily Kos re: Sangamo's trials:

http://www.dailykos.com/story/2012/02/28/1069145/-First-Real-Hope-for-Eradication-of-HIV?via=tag

And a story from poz.com, but I couldn't find it there, so posting it.  Looks like for the second (not heterozygous) trial you need to have been 1) infected in the last 5 years, 2) have T cells above 600 and 3) not have antibodies to the adenovirus, so that you don't kill off the newly transfused cells.

I'm going email Grace at Quest in San Francisco (I'm in Berkeley) and try to learn more about it.

Here's the poz story:

March 2012


Helping to Find a Cure for AIDS

by Bill Strubbe

Participating in clinical trials can bolster your health—and that of the whole community.

Like many people living long-term with HIV, Gregg Cassin (who tested positive in 1986 but believes he contracted the virus five years earlier) avidly followed reports of Timothy Brown, the first man cured of HIV. Brown, an American otherwise known as the “Berlin Patient” for the city where he was treated, required a stem cell transplant for his leukemia. He was given cells (which reseeded his entire immune system) from a donor with a genetic variant that makes people virtually resistant to HIV. Nearly five years later, Brown remains HIV-free.

When Cassin heard that a University of California at San Francisco (UCSF) clinical trial was developing an HIV therapy based on lessons learned from Brown’s case, he decided to enroll. That’s when he discovered something new about his own HIV.

One arm of the study located in San Francisco, where Cassin lives, was looking for people with one copy of a mutated gene—the CCR5 delta-32 variant—that makes HIV progress more slowly. The Berlin Patient’s stem-cell donor had two copies of that mutation.

Survivors of the Black Death, the plague that wiped out half of 14th-century Europe, are thought to have passed the genetic variant to their descendants. The mutated gene shortens and disables the CCR5 protein on the surface of CD4 cells, which HIV generally needs in order to enter and infect the cells. About 1 percent of people of Northern European descent inherit two copies of the variant, one from each parent. Those people are called homozygous, and like the stem cell donor in Brown’s case, they do not contract HIV (unless their virus can attach to a different CD4 surface protein, CXCR4). People who inherit just one copy of the gene are called heterozygous. They can contract HIV, but the virus generally progresses slowly in them.

“I never thought I would have the mutation,” Cassin says. “Early in my HIV I had low CD4 cell counts, so I didn’t think I was a slow progressor. I was surprised when the researchers called me and excitedly told me I was heterozygous”—his DNA contained one copy of the mutated gene.

The UCSF study, led by Jay Lalezari, MD, removes CD4 cells from the subject’s blood and genetically alters them. The gene responsible for CCR5 production is removed using a new molecular “scissors” called “zinc finger nuclease” (ZFN) developed by Sangamo BioSciences. The modified cells are then stimulated to reproduce, and they’re re-infused into the participant’s body to propagate new CD4s with the gene variant. After several months, it is hoped, the subject stops taking HIV meds and voila! The altered cells, lacking the most common doorway for HIV to enter, are able to keep the virus in check.

As Cassin says, “If this [idea] works, I just might be able to stop taking HIV meds forever.”

In his San Francisco clinic, Lalezari lays out the trial plan: “First we have to figure out if [the ZFN strategy] works, how it works and in whom it works. Then we can figure out how to make it work for more people. The prize remains a more broadly effective therapy.”

Cassin’s group is not the first to undergo the treatment. “The original group were not heterozygous,” Lalezari says. A small number of heterozygotes were later recruited, he says, after especially promising results in one heterozygous man in the initial group. “Heterozygote patients already have 50 percent of their CCR5 genes removed courtesy of Mother Nature,” Lalezari explains. “So half the work has already been done for us.” In other words, researchers only have to coax participants’ immune systems into converting half their genes to versions that can deny HIV a docking station on CD4 cells.

Being heterozygous wasn’t the only qualification Cassin had to meet, though. He also had to lack antibodies to a specific cold virus (adenovirus). As Lalezari puts it, “The adenoviral vector is the means by which the zinc finger protein is delivered into the nucleus of the CD4 cells where the CCR5 gene resides.” High levels of the antibodies would kill off the infused cells.

Cassin, who did not have those antibodies, received his modified cell infusion in early January. He says he was “a bit anxious” about whether taking in genetically modified cells might cause harmful effects down the line.

Lalezari is reassuring about potential side effects. “So far,” he says, “the therapy is safe and well-tolerated. Aside from a flu-like response in the day or two after the infusion, we haven’t experienced any clinical side effects. We have some patients out now to two years, so we remain comfortable with the protocol’s safety.”

On January 9—the same day Cassin got his infusion—Sangamo announced that Phase I trials were so safe and effective that Phase II studies, involving both heterozygous people and positive people who don’t have the genetic mutation at all, are starting sooner than expected.

Researchers are seeking trial participants newly diagnosed with HIV and not necessarily heterozygous. “Anyone who has been HIV positive for less than five years, with CD4 cells above 600, could potentially be eligible right now,” Lalezari says. “The day before the gene therapy infusion, this group will get a small dose of chemotherapy to try to improve the [absorption] of the gene modified cells.”

Meanwhile, Cassin balances hope and realism. “The researchers have made it clear to me that the trial is experimental,” he says. “The worst case scenario is that my immune system gets a boost that leaves my body a little less burdened.”

His trial participation is motivated by other HIV-positive people, both living and dead. “The day I found out that I was accepted in the trial,” Cassin says, “I thought about all the friends I’ve lost, how far we have come, and of moments like this that gave us hope that we were going to make it. All at once those friends’ absence—and oddly their presence—was deeply felt.”

HOW TO:
Support HIV research through clinical trials
If people with HIV had not agreed to be guinea pigs for drug development, we wouldn’t have today’s wide choice of treatments. For some people—those who’ve run out of treatment options because of resistance to HIV meds, for example—joining a trial allows you to use drugs before they are approved. Many trials offer financial reimbursement as well.

But joining a study can seem scary, and the benefits minor. Gregg Cassin, a participant in the UCSF zinc finger nuclease gene trial, tried unsuccessfully to interest others in joining. He says: “I think the reasoning must be, ‘I am doing pretty well on the meds, and how am I going to benefit?’”

By doing careful research and consulting your doctor, you can make an educated decision about entering a trial—and know that you are advancing HIV science.

For help considering all sides of the question, search “joining a clinical trial” (in quotes) at poz.com (click here) or go to poz.com/theroadtowashington to learn more.

Join a Study
Zinc finger nuclease trial
Tests whether ZFN gene therapy will let positive people remain undetectable off HIV meds. In the Bay Area, contact Grace Gonzaga, grace@questclinical.com; 415.353.0212. Elsewhere, search 5B-728-T at clinicaltrials.gov.

Find and join other studies
For comprehensive trial info, go to:
clinicaltrials.gov
aidsinfo.nih.gov
actgnetwork.org
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on March 02, 2012, 01:55:59 pm
So I called Quest to inquire about the trial.  It was interesting.  The "Trenton" patient (the one who went UD in the first trial) as a) heterozygous b) newly infected c) had high T-cells and d) had a low adenovirus antibody titer.

Quest/Sangamo uses the adenovirus 5, a common cold virus, to deliver the ZFNs to your T-Cells.  If you've had a cold -- or thrown off a cold -- recently, you'll have a high level of adenovirus antibodies.  This will kill the delivery mechanism for the modified cells and it'll stop the modification to your T-Cells from happening.   This is disqualifying the majority of applicants.  This level of this antibody is seasonal so being disqualified now doesn't mean it will also be so.

So they are looking, in these two trials, to replicate the Trenton patient.  First trial: get heterozygotes.  Second trial:  look for people that have T-Cells above 600, infected in the last 5 years, and low adenovirus antibodies.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Dr.Strangelove on March 03, 2012, 02:37:06 pm
These are really great news.
Thanks for keeping us updated.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: ichigo_kun on March 09, 2012, 05:35:40 pm
Pathway to a Cure: Positive Results Continue for Sangamo’s CCR5 Gene Therapy
by Tim Horn
Genetically modifying CD4 cells to knock out the CCR5 coreceptor resulted in significant CD4 count gains and notable viral load reductions while off antiretroviral (ARV) therapy, according to new data from a clinical trial of Sangamo Biosciences’ zinc finger nuclease (ZFN) therapy SB-728-T, reported Thursday, March 8, at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle.

Background

After HIV binds to the CD4 protein on CD4 cells, the virus must then latch onto another receptor on the cell’s surface—either CCR5 or CXCR4. Usually, when people contract HIV, their virus starts off using the CCR5 receptor. Later on, as HIV disease progresses, the virus can switch to the CXCR4 receptor—this occurs in about 50 percent of treatment-experienced patients.

Selzentry (maraviroc), a U.S. Food and Drug Administration (FDA)–approved ARV, works by blocking the interaction between CCR5 and HIV, ultimately retarding the virus’s ability to infect CD4 cells. SB-728-T, a zinc finger DNA-binding protein transcription factor, goes one step further—it blocks the gene responsible for making CCR5, mimicking a naturally occurring human mutation that renders individuals largely resistant to the virus.

This mutation, dubbed CCR5 delta-32, appears to have no harmful effect in the human body. In addition, a study published in the journal Blood in December 2010 reported that an HIV-positive person with leukemia was cured of HIV when he received a bone marrow transplant from a “matched” donor who had inherited this delta-32 CCR5 mutation from both parents. (When the mutation is inherited from one parent, CCR5 is produced, but at low quantities and is associated with slower HIV disease progression. When the mutation is inherited from both parents, which is very rare, little or no CCR5 is expressed on CD4 cells, rendering the cells impervious to forms of HIV that use the CCR5 receptor to enter cells.)

Sangamo’s gene therapy approach has both therapeutic and curative potential. At present, only Sangamo’s therapeutic-focused CCR5-knockout SB-728-T has entered clinical trials.

Therapy involves removing CD4 cells from patients’ blood, treating the cells with SB-728-T to knock out the CCR5 gene, multiplying the cells in the lab, then transplanting the HIV-resistant genetically modified cells back into the body. 

Fully curing HIV will be a bit more complicated, as it ultimately requires replacing the entire CD4 population with HIV-resistant cells, not merely creating a small reservoir of protected cells. A curative approach will likely involve removing and treating stem cells with CCR5 and possibly CXCR4 knockout genes, administering high-dose chemotherapy to wipe out the existing HIV-susceptible immune system, followed by transplanting the modified stem cells to rebuild an immune system that is resistant to the virus.

In one therapeutic study reported at last year’s CROI in Boston, Jay Lalezari, MD, of Quest Clinical Research found that infusions of CD4 cells modified using SB-728-T were safe, disseminated throughout the body and associated with CD4 cell increases in a small group of HIV-positive patients with “immune-discordant” responses to ARV therapy—in other words, they had undetectable viral loads but limited CD4 gains despite several years of treatment.

Another study, detailed in September at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago, reported on six patients—none of whom was an immune-discordant responder to ARV treatment—who underwent a treatment interruption one month after receiving SB-728-T-modified infusions of their own CD4 cells. In three of the six subjects, significant viral load reductions were documented during the treatment interruption phase of the study. Viral load levels also went undetectable in one patient.

CROI Update

Pablo Tebas, MD, of the University of Pennsylvania and his colleagues provided an update on the six study volunteers who underwent a treatment interruption following SB-728-T treatment, along with the 15 immune-discordant ARV treatment responders. All patients received a single infusion of 5 billion to 30 billion CD4 cells modified with SB-728-T.

The average age of the immune responders—those who were otherwise responding well to ARV treatment—was 46. All were male with CD4 counts averaging more than 900 at the start of the trial. Among discordant responders, the average age was 48 and they averaged 335 CD4 cells at the start of the study; two of the 15 were women. The average CD4:CD8 cell ratio—a measure of immune system balance that is typically low in people living with HIV—was 1.4 among the six immune responders and 0.7 among the 15 discordant responders at baseline (normal is generally 1.0 or higher).

SB-728-T treatment continues to be safe and well tolerated. Severe adverse events were rare; the vast majority were mild-to-moderate in intensity and were mostly seen within 24 hours following infusions. The most common infusion-related side effects were chills, fever, headache and excessive sweating.

CD4 cell increases were noted in both groups. In the immune-responder group, CD4s shot up more than 1,500 points following the infusion. By day 30, CD4 cell counts in this group were still 1,000 points above their pre-infusion levels.

Less substantial, but statistically significant, gains in CD4 cells were seen in the discordant responder group as well. After initially seeing their CD4 counts increase 500 points following infusion, the group saw their average numbers of CD4s consistently remain above pre-infusion levels for about a year. 

CD4:CD8 ratios normalized in the discordant responder patients and increased in the responder patients.

Tebas and his colleagues also noted elevated levels of cellular messengers—the CD4 cell cytokines IL-2, IL-7 and IL-15—immediately following the infusions, which may likely explain post-infusion symptoms and, more positively, the rapid expansion of CD4 cells.

The researchers also reported that the ZFN-modified CD4 cells could be detected in blood samples for over a year, ranging from 90 days in one patient to more than 700 days in another. Also of importance, the modified cells showed evidence of traveling and taking up residence in gut tissue, an important HIV reservoir in the body.

Tebas reiterated the results of the treatment interruption experiment—conducted only in the immune responder patients—reported at the September ICAAC conference. After therapy was stopped, viral loads initially increased in all patients. This was followed by viral load drop—reductions ranged from 0.8 to more than 2.0 log—in three of the six patients.

The one patient who saw his viral load decrease to undetectable levels entered the study carrying the natural CCR5 delta-32 mutation on one copy of his CCR5 gene, with the infusion facilitating an even more substantial HIV-CCR5 blockade. This finding, coupled with observations from the other five patients who initiated a treatment interruption, suggested to Tebas and his colleagues that control of viral load in the absence of therapy correlated with levels of circulating CD4 cells in which both copies of the CCR5 gene (bi-allelic) underwent modification as a result of SB-728-T therapy.

Finally, Tebas said that levels of circulating proviral DNA in CD4 cells—a measure of the viral reservoir—increased four times and nine times in two of the six patients, respectively, during the treatment interruption. However, these increases reversed when ARV therapy resumed.

In conclusion, Tebas said that data from these studies involving discordant responders and immune responders is “promising and warrants further evaluation. Further clinical development of SB-728-T,” he added, “will aim to maximize patient exposure to CCR5 bi-allelic modified CD4 cells in two ongoing clinical trials.”
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on March 19, 2012, 11:32:37 am
So I went and got myself screened for the second Sangamo trial (I screened for the first and wasn't a heterozygote).  Most people are failing the screening because they have a high level of the adenovirus 5 titer.  Quest said that this titer is seasonal -- if you've been around kids a lot you probably have a higher level.  Results take about a month (first they check T-Cells / VL.  If that's OK for the trial, they go on on to test the A5 antibody).
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on March 22, 2012, 09:07:56 am
It sounds like adding Chemo didn't help.  Hopefully the purification step is added in future trials talked about in this article here:

http://www.aidsbeacon.com/news/2012/03/19/chemotherapy-plus-stem-cell-transplantation-is-not-sufficient-to-cure-hiv-aids-croi-2012/
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on March 22, 2012, 11:42:05 am
Yeah, but your link has nothing to do with the current Zinc Fingers/Sangamo phase II trial. Scared me for a minute... :o Zinc Fingers is the topic of this tread. Some info on the current Sangamo trials should be coming out in a few months...July?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on March 22, 2012, 04:30:39 pm
Yeah, but your link has nothing to do with the current Zinc Fingers/Sangamo phase II trial. Scared me for a minute... :o Zinc Fingers is the topic of this tread. Some info on the current Sangamo trials should be coming out in a few months...July?

Ah, ok that's good, whoops
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on March 22, 2012, 05:08:58 pm
Yeah, that was a different trial.  Didn't involve resistant stem-cells treated with ZFNS.

When I was getting screened for the Cytoxan/ZFN trial the other day I asked a lot of questions -- turns out the first heterozygotes are now at the point of stopping their meds and then waiting to see what happens.   Seems to me (I have no real knowledge) that by the end of the summer we'll know if this is working for them or not.  I would imagine that if the results are all the same (works or doesn't) we'll know sooner than if the results vary between participants.

I still think it's a shot in the dark.  But if it works...wow.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on March 24, 2012, 06:11:16 pm
Geobee, don't think the CCR5 gene modification is a shot in the dark. BUT, I don't think the current trials using CD4s is going to get us to a functional cure, but somehow I do see it as a posible end game for AIDS, although perhaps a yearly treatment will be envolved. If the Sangamo people start using STEM CELLS and modify something in the range of 90%, then THAT will be a game changer. If I were a betting man, I'd bet on Calimmune with its RNAi to do the trick for a functional cure...RNAi seems to have more knock-out power then Zinc Fingers. Although I'm still praying for Sangamo to anounce breakthroughs this summer/fall.

I have been a medical doctor for the past 10 years and was dxed positive 4 months ago... perhaps I'm still I'm just FULL of HOPE. Hope not.  ;)

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on March 24, 2012, 06:58:36 pm
Geobee, don't think the CCR5 gene modification is a shot in the dark. BUT, I don't think the current trials using CD4s is going to get us to a functional cure, but somehow I do see it as a posible end game for AIDS, although perhaps a yearly treatment will be envolved. If the Sangamo people start using STEM CELLS and modify something in the range of 90%, then THAT will be a game changer. If I were a betting man, I'd bet on Calimmune with its RNAi to do the trick for a functional cure...RNAi seems to have more knock-out power then Zinc Fingers. Although I'm still praying for Sangamo to anounce breakthroughs this summer/fall.

I have been a medical doctor for the past 10 years and was dxed positive 4 months ago... perhaps I'm still I'm just FULL of HOPE. Hope not.  ;)

Interesting, had to google Calimmune thanks.

I'm not sure what half of the following means, but it sounds good!
__________________________________________
http://rnaitherapeutics.blogspot.com/2011/07/solid-calimmune-dna-directed-rnai.html

"The Calimmune approach: A non-toxic, H1-driven shRNA targeting CCR5

The reason why I feel that Calimmune’s approach may have better prospects is that it has fully accounted for the U6-related shRNA toxicities and selected an H1 promoter-based RNAi expression cassette that was shown to be both safe/stable and, equally important, highly efficient in CCR5 knockdown in human and rhesus HSC-derived cells. Also, I like the fact that it is an RNAi trigger, and not a ribozyme, that is targeting CCR5, as I believe this to be the more efficient knockdown modality."
__________________________________________

I confirmed through a medical friend that Calimmune trials are most likely starting in 2012 in deed.
(San Fran)

If you had the choice to do the current Zinc Finger WITH Chemotherapy trial now or wait for  the new Calimmune trial this summer/fall, which one would you do?

They want you to be undetectable before you can start the Zinc Finger Gene Transfer trial.  I wonder if it's the same thing for the Calimmune trial?   For now I'm going to start the Cenicriviroc meds trial.   Check out the benefits!   I just got my blood drawn and waiting for results before I start. (will take 4 weeks)  I've only been poz for a month so haven't started anything yet.

http://www.aidsmeds.com/archive/cenicriviroc_2656.shtml

"Cenicriviroc primarily works by binding to a receptor on the membrane of CD4 cells called CCR5. Once it does this, HIV cannot successfully bind with the surface of CD4 cells, thus preventing the virus from infecting healthy cells. It also binds with another receptor called CCR2. By blocking this receptor, which has been linked to inflammation in the body, cenicriviroc may also reduce the risk of certain non-AIDS health conditions that are becoming increasingly common among people living with HIV, including cardiovascular disease, neurologic problems, metabolic complications and some cancers. "

So yeah staying on topic, once I'm undetectable via Cenicriviroc, I wanted to do the Zinc Finger/Chemo trial.  I'm going to have to ask about the Calimmune one now though to see which one sounds more promising!

Hell, maybe we can do BOTH trials at the same time?  You can already over lap others we'll see what they say.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on March 24, 2012, 07:48:09 pm
I'd do Callimune. And I would also do Zinc Fingers Stem Cells (its in their pipeline). Callimune has David Baltimore(google). I 'd do everything that looks promising. I think Callimune is going to start with stem cells...right? I like permanence. You can't get that with cd4s.

The way I see it is that we are at a point where the hits will be getting closer and closer to the bullseye.

The following is in another thread, but since you mentioned clinical trials ans I mentioned Baltimore I need to go further: David Baltimore and Balasz came up with vectored immunophrophylaxis about a year ago. Basically, using a vector, muscle cells start pumping out broad neutralyzing antibodies. Clinical trials MIGHT start this year. They have this as Preventive (yes!) and alternative to clasical vaccinology but I think it can also be used as a therapeutic vaccine. Its simple really, by getting the body to produce the same
antibodies that elite controllers use MIGHT make me into an elite controller and thus
 a functional cure. If I could, Id sign up for this trial also.  ; ;)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on March 24, 2012, 09:37:26 pm
Hey Tadeys --

Yeah, I think all four (Sangamo Tcell, Sangamo HSC, Callimune, Balasz)  are really encouraging -- just didn't want to be all pie-in-the-sky about it.  From what I could gather from Quest in SF, doing the Sangamo trial might rule me out of the HSC trial.  Also, most people (75% to 80%) are not qualifying for the Sangamo TCell trial because of the high level of Adenovirus 5 titer.  They said they could use a different vector in the future but, of course, this would take time. 

For myself, I'm expecting not to get into the TCell trial because of that A5 thing.  They said that this was not a restriction of the HSC trial.  They also said that  HSCs were harder to work with. 

I think we'll know a lot more in about 3 months as the first heterozygotes have now stopped their meds.  It took 11 weeks for the "Trenton" patient to become UD.  He actually went back on meds because his VL test results at week 11 came back AFTER the 12 week STI trial period ended. Whoops! But if the current crop of heterozygotes go UD and stay there (or even if 1 or 2 do), it's going to be very big news indeed.

George

PS:  4 mos in, huh?  Hope it's going well.  I've been poz for about 3 years. Anyway, the first year was a blur -- but life is good now.  It gets better.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on March 24, 2012, 10:07:55 pm
Awesome, yeah I've only been poz for 3 weeks, and I already dived into a clinical trials.   I'll do any and all promising trials that sounds promising, sign me up.  I'm at Quest in SF too by the way :)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on March 25, 2012, 05:26:33 am
These past few months HAVE been a blur. What has kept me going is news on research.There are SOOOO many things out there for HIV, with about a dozen or so posible cures--at least in pre-clinicals and a few clinicals. If only the whole process from conception to Rx were faster. Hope the Hagan bill passes to speed things up a bit. ;)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on March 29, 2012, 01:34:04 am
RICHMOND, Calif., March 28, 2012 /PRNewswire/ --Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that Edward Lanphier, Sangamo's president and CEO, will provide an update on the progress of Sangamo's ZFP Therapeutic® development programs and an overview of the company's business strategy at 8:40 am ET on Wednesday, April 4, 2012, at the 11th Annual Needham Healthcare Conference which will be held in New York City.
The presentation will be webcast live and may be accessed via a link on the Sangamo BioSciences website in the Investor Relations section http://investor.sangamo.com/index.cfm under Events and Presentations. The presentation will be archived on the Sangamo website for two weeks after the event.

http://www.sys-con.com/node/2225346
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on March 29, 2012, 01:36:23 am
RICHMOND, Calif., March 28, 2012 /PRNewswire/ --Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that Edward Lanphier, Sangamo's president and CEO, will provide an update on the progress of Sangamo's ZFP Therapeutic® development programs and an overview of the company's business strategy at 8:40 am ET on Wednesday, April 4, 2012, at the 11th Annual Needham Healthcare Conference which will be held in New York City.
The presentation will be webcast live and may be accessed via a link on the Sangamo BioSciences website in the Investor Relations section http://investor.sangamo.com/index.cfm under Events and Presentations. The presentation will be archived on the Sangamo website for two weeks after the event.

http://www.sys-con.com/node/2225346

Exciting, let's hope there is good news/progress. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on April 04, 2012, 04:26:44 am
Here's the conference we'll be able to listen to in a few hours. (4 hours as of this post)   I did a test, it seems this stream only works using Internet Explorer.   I tried Firefox and Chrome and it didn't work.

http://www.wsw.com/webcast/needham51/

------------------------------------------------------
Username: needham
Password: healthcare
------------------------------------------------------

Scroll down to:  Wednesday, April 4, 2012 8:40AM Sangamo BioSciences Inc
http://wsw.com/webcast/needham51/sgmo/
(you must be logged in already via the lobby page in first link)


Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on April 04, 2012, 09:38:14 pm
Here's the conference we'll be able to listen to in a few hours. (4 hours as of this post)   I did a test, it seems this stream only works using Internet Explorer.   I tried Firefox and Chrome and it didn't work.

http://www.wsw.com/webcast/needham51/

------------------------------------------------------
Username: needham
Password: healthcare
------------------------------------------------------

Scroll down to:  Wednesday, April 4, 2012 8:40AM Sangamo BioSciences Inc
http://wsw.com/webcast/needham51/sgmo/
(you must be logged in already via the lobby page in first link)


The last few minutes of Q & A are very interesting.  (sounds promising!)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on April 05, 2012, 05:53:31 pm
Hey JazJon --

The people from Quest called the other day re: a third trial they are doing (the first two being the Sangamo hetero and enhanced uptake trials).  This third trial is from CalImmune and it's similar to Sangamo's in that it's a CCR5 knock out strategy.  It's different in that it uses stem cells and T-Cells, not just T-Cells.   Since you've been talking to the Quest people, it might be worth an inquiry.  I'm going in on Monday to learn more about it.  I'll post a blurb after the meeting with Quest.

There's not much info out there on CalImmune -- can't quite figure out why.  They've got some heavy hitters (i.e. nobel laureate David Baltimore) on the team. Seems a little scary to me to mess around with stem cells-- but if I don't qualify for the Sangamo trial (which is likely) I'll probably go for the CalImmune trial if I can get in.

George
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on April 05, 2012, 07:11:47 pm
Hey JazJon --

The people from Quest called the other day re: a third trial they are doing (the first two being the Sangamo hetero and enhanced uptake trials).  This third trial is from CalImmune and it's similar to Sangamo's in that it's a CCR5 knock out strategy.  It's different in that it uses stem cells and T-Cells, not just T-Cells.   Since you've been talking to the Quest people, it might be worth an inquiry.  I'm going in on Monday to learn more about it.  I'll post a blurb after the meeting with Quest.

There's not much info out there on CalImmune -- can't quite figure out why.  They've got some heavy hitters (i.e. nobel laureate David Baltimore) on the team. Seems a little scary to me to mess around with stem cells-- but if I don't qualify for the Sangamo trial (which is likely) I'll probably go for the CalImmune trial if I can get in.

George

Ah! Thanks for clearing that up.   The CalImmune trial sounds even more interesting.  I'm willing and ready to volunteer for either trial as soon as I'm Undetectable. (which should be in a month or two)   I'm starting Quest's Cenicriviroc trial in a few weeks for starters.  It will be my first time on meds, but I'm told people have zero side effects so far, and it's been very tolerable.  The anti inflammatory properties are fascinating.
http://www.aidsmeds.com/archive/cenicriviroc_2656.shtml
I'm just waiting for final blood work to come back.  So far so good though from my initial/partial results and based on my regular doctors blood work.

Once I'm UD, I'm ready to be part of which ever trial sounds more promising.  (please keep us updated)  I really hope to be part of the first proud wave of people with a functional or actual cure.   If it doesn't stick, I'd be happy enough with a boosted immune system at the very least. (new Elite controller status?  we'll see)

I look forward to learning and hearing more about all this.

Progress marches on...........
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on April 10, 2012, 12:37:35 pm
So I went to Quest to find out more about the CalImmune study.  There will be 3 cohorts --

1.  Modified T-Cells and Stem Cells, no chemo to increase uptake
2.  Modified T-Cells and Stem Cells, with mild chemo to increase uptake
3.  Modified T-Cells and Stem Cells, with medium chemo to increase uptake

This brings to 5 the number of gene theraphy trials I know of at Quest, the other two are:
4.  Heterozygotes and Sangamo-modified T-Cells and
5.  Non-hetero and Sangamo-modified T-Cells and Cytoxan to increase uptake

The CalImmune trials will start in the summer.  The Sangamo trials are currently underway.  As I mentioned earlier, some of the heterozygotes (# 4) have stopped their meds after receiving their infusion of modified cells.   Can they get UD like the "Trenton" patient (a heterozygote)? If they can, then they know that he wasn't a fluke.  Uh, wow.

Other thoughts --

The earlier trials with something similar to CalImmune were disappointing in that many of the infused cells died off after infusion.  This could have been because regular T-Cells were infused along with the modified cells so that no "space" was available for the modified cells.  These new trials are aimed at increasing the uptake.

Once you get participate in a gene therapy clinical trial, you may be precluded from participating in other gene trials.  Also, as I mentioned in an earlier post, many people are being screened out of the Sangamo non-hetero trial because of their high level of adenovirus (A5) antibody.  The adenovirus delivers the treatment; a high level of that antibody renders the treatment ineffective.  Also, if you were a patient from the first trial and wanted a reinfusion, you will have to wait until the level of A5 AB -- increased because of the initial infusion -- goes down.

Sangamo is also working on a stem-cell version, I don't know much about this other than the year-old articles which focused on Paula Cannon's work at USC.

Much of this has been made possible because of California's Proposition 63, which put $3B into stem-cell research and created the CIRM, California Institute of Regenerative Medicine.

Head scratcher:  I can't figure out why all the patients receiving the modified T-Cells in the first trial didn't go UD.  They all had some immune T-Cells, right?  Why didn't HIV wipe out the non-immune T-Cells and leave the immune T-Cells?  Is it because the body keeps producing the non-immune cells?  If so, can they just increase the ratio of immune cells (which fight HIV) to non-immune cells, will that be enough to overwhelm the amount of virus in the body? Hopefully this question will be answered by trials 4 and 5.

I once saw a you tube video of Paul Cannon describing how she felt that HIV was a genetic disease in that it integrates with your own DNA (there's already a lot of other "junk" in our DNA from other viruses).   She described gene therapies as appropriate because HIV was a genetic disease. Perhaps there will be a preventative vaccine that will mount a strong immune defense to beat back a new infection.  But for those of us already infected, I can't figure out how a
therapeutic vaccine alone will rid us of the HIV already integrated into our DNA. 

Dr. Margolis and others are at working trying to attack latency/reservoirs.  Again, seems like this is a tall order -- how do you rid the body of every last HIV virion? Isn't just one virion enough to recreate full-blown infection?  Seems to me that even if we can reduce the reservoirs, we're going to need gene therapy to create at least some immunity.

Perhaps these trials will lead to a cure, perhaps not. But is sure seems like a good option for people that meds have stopped working for. 

But, if it works, will this be a therapy for all people?  Can we really imagine a scenario where people in all parts of the world extract their blood through apheresis
, ship it to some lab, get some chemo, and then get reinfused?  I can imagine it.  Yes, there will be cost and delivery hurdles -- but taking meds forever is not going to work either.  Death rates have dropped off because of the cocktail, but more and more people are living with HIV every year.  If a solution is known to cure people, the manufacturing and distribution process will improve driving costs down and making it widely available to all.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: xman on April 10, 2012, 02:50:48 pm
it is indeed possible that one virion is not capable to reseed the entire infection. if we consider that a certain viral load is necessary for transmission perhaps even in an established infection a minimum amount of virus is essential to keep the population alive. it is only a theory but with luck not every virion must destroyed to be cured.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on April 10, 2012, 09:03:33 pm
Excellent update geobee, thanks for the very informative breakdown.  I'm looking forward to being part of these new trials.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on April 11, 2012, 01:04:38 am
Sure hope you're right X-Man -- that we don't have to get at every virion -- that we can somehow get at most of them and let our immune system do the rest.  I thought the article you posted (thank you) re: the small molecule formulations of Reyataz and Truvada was really interesting.  If we could find drugs that would effectively go after the reservoirs that would sure be a game changer.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Dr.Strangelove on April 11, 2012, 11:09:38 pm
Quote
Head scratcher:  I can't figure out why all the patients receiving the modified T-Cells in the first trial didn't go UD.  They all had some immune T-Cells, right?  Why didn't HIV wipe out the non-immune T-Cells and leave the immune T-Cells?  Is it because the body keeps producing the non-immune cells?  If so, can they just increase the ratio of immune cells (which fight HIV) to non-immune cells, will that be enough to overwhelm the amount of virus in the body?

It does make sense. The reason why the Berlin Patient was 'cured' was because all of his T-cells were immune and HIV had no way to replicate without CCR5-carrying T-cells. But in the Sangamo trials, they inject immune T-cells which co-exist with the native T-cells that are not immune. So, without HAART treatment HIV can use those cells to replicate just like it does in any other poz person without treatment. HIV will simply ignore the immune T-cells because they lack CCR5. Just like HIV ignores any other non T-cells. It's not that the immune T-cells 'go after' HIV. They are not a anti-retroviral drug.
As for why doesn't HIV wipe out the non-immune cells: How fast does HIV wipe them out usually? After HIV infection it usually takes years until the CD4s drop below 200 and the person develops AIDS.
Why should HIV kill the non-immune T-cells any faster in the presence of immune T-cells?

Quote
But for those of us already infected, I can't figure out how a
therapeutic vaccine alone will rid us of the HIV already integrated into our DNA.
A therapeutic vaccine would have to animate the body to produce the right kind of antibodies. That is broadly neutralizing antibodies that kill off pretty much all of the virus in the blood. The vaccine would make the person a kind of elite controller that manages to keep the viral load low (possibly UD) with his immune system.

Quote
Isn't just one virion enough to recreate full-blown infection?  Seems to me that even if we can reduce the reservoirs, we're going to need gene therapy to create at least some immunity.
A single virion can potantially recreate a full blown infection but in most cases it won't be necessary to get rid of every single virion. Our immune system is well able to fight HIV. After seroconversion the viral load skyrockets, but as soon as the immune system creates antibodies against HIV the viral load goes down. These antibodies are effective against HIV. They keep it in check for many years - but they are not good enough to eradicate every single virus and eventually HIV wins. This gives me hope because it means that the body may be able to take care of a few leftover virus after flushing the reservoirs.
In one of the CROI 2012 talks, Prof. Sharon Lewin mentioned that there are rare cases where poz people after long successful (=UD) treatment stopped taking drugs and were able to control HIV with their normal immune system. Their VL was stable without any further treatment.

Quote
But, if it works, will this be a therapy for all people?  Can we really imagine a scenario where people in all parts of the world extract their blood through apheresis, ship it to some lab, get some chemo, and then get reinfused?  I can imagine it.  Yes, there will be cost and delivery hurdles -- but taking meds forever is not going to work either. If a solution is known to cure people, the manufacturing and distribution process will improve driving costs down and making it widely available to all.
After my initial excitement, I don't see this approach as 'the' solution anymore. Surely, the ex-vivo method that Sangamo is exploring now is just a first step. I don't think it will ever be widely applied. It's just too complicated of a procedure and I don't see how they can make it much more cheaper. It's not like a drug, that can easily be mass produced. Also, I don't think their current method will be able to reproduce the results of the Berlin patient.
Maybe it will be a solution for people who have no other option.
I am more optimistic about the modified stem cells. This would be a one-time procedure.
Anyway, these are my thoughts.
 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on April 12, 2012, 01:06:48 pm
Here's an interesting article re: CalImmune --

http://rnaitherapeutics.blogspot.com/2011/07/solid-calimmune-dna-directed-rnai.html

Interesting post, Dr. SL.  I thought that the infused modified T-Cells *do* have an antiviral effect.  The theory is that not all of your T-Cells need to be modified -- just about -15-20% or so to bring the viral levels down.  Anyway, that's the thinking behind the two Sangamo trials underway at Quest.  One of the heterozygotes went UD in the first trial because nature gave him an advantage -- he had double the number of modified cells.  Cytoxan should increase the uptake for the non-heteros.

We'll know soon enough if it works as some patients have gotten their infusions and stopped their meds. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on April 19, 2012, 03:46:07 pm
Recent slide presentation by Dr. Cannon (love her):

http://dcfar.med.miami.edu/documents/Dr_Cannon_-_CCR5_gene_knockout_in_hematopoietic_stem_cells_(1).pdf

The latter half is new and interesting.  Once again she says these mice go undetectable in 12 weeks after the stem cell transplant.

Of course, modifying T-Cells might work.  In about 2 months it'll be 12 weeks since the first heterozygotes stopped taking their meds.  That should be enough to know whether the T-Cell treatment works or not.  Of course, the results may come out long after that, particularly if they are not good.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sensual1973 on April 20, 2012, 04:10:29 am
mice.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: bmancanfly on April 20, 2012, 10:15:33 am
There's never been a better time to be a mouse with HIV.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on May 04, 2012, 11:40:03 am
Reading through the Q&A on Sangamo's quarterly conference call I found, from Ed Lamphier (CEO):

"I think its realistic to think that we will have those trials accrued by the end of the year and data in the first half of 2013 is a realistic expectation."

This means that the data for the current trials (the hetero trial and the Cytoxan trial) will be available next year.  I'm guessing that they'll release the info at CROI 2013.

Also very interesting was this answer:

"As it relates to HIV however, I think that’s a program that we will view as something we would like to partner for pivotal trials and for commercialization. It’s a large patient population, therefore a fairy significant commercial manufacturing undertaking and its something that we’d like to bring a partner on for pivotal trials and commercialization."

What I found intriguing was that he's already thinking down the road -- towards manufacturing and commercialization.   Hmmm......

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: wherehope on May 18, 2012, 11:35:08 pm
Felt excited at first, but after read details feel down again. The modified cd4 will die after years and maybe few years, even functionally cured then need to re-cure again after a "short" period, regarding the cost and chemotherapy each time. The newly produced CD4 of immune system is still the same as the old ones with CCR5 on it. This is different than elite controller whose all 100% CD4 always lack ccr5 all time. Maybe the stem cells have more hope since it maybe extend the HAART free period longer?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on May 19, 2012, 06:42:47 am
Felt excited at first, but after read details feel down again. The modified cd4 will die after years and maybe few years, even functionally cured then need to re-cure again after a "short" period, regarding the cost and chemotherapy each time. The newly produced CD4 of immune system is still the same as the old ones with CCR5 on it. This is different than elite controller whose all 100% CD4 always lack ccr5 all time. Maybe the stem cells have more hope since it maybe extend the HAART free period longer?

Uh....no.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: younghopefulpoz on May 19, 2012, 10:37:11 am
Maybe you should try bone marrow transplant, like Timothy brown.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on May 19, 2012, 01:05:25 pm
Uh....no.

An Elite controller and someone who lacks the CCR5 gene are 2 separate entities. One has to do with antibodies and the other, with receptors on their cells.                       1) Every Elite contoller is HIV positive; they just CONTROL their infection to the point where it hardly does any harm to  their body.
2)It is dificult to find a person with the CCR5 mutation ( of BOTH copies) who IS HIV positive...they are pretty much immune from being infected with an HIV-1 Virus that uses ONLY the CCR5 receptor.
 
Also, ah, That Cd4 cells die out with in an X amount of time... Nothing new. Now Stem Cells do not die out and are always multiplying. Sooooo, for a cure:  1) More is better: the more cells without the CCR5 receptor the better. Knocking-out both receptors (CCR5 and CX4) would be best. 2) Stm Cells SEEM far more superior then cd4s for a CURE. Do we need both of these for a cure of sorts? Nobody knows for sure. Scientist stopped finding HIV In Brown a few months after the transplant...but he had virtually a new immune system after the treatment. The Trenton patient went undetected with just a few percent of his CD4s being zinc fingered...:).... don't get carried away AND please incluye a link next time. :P                                                                                                                    And another thing, would'nt count  on any one technique as being capable in and of itself in getting us to a cure. A combination of Medication + gen therapy + therapeutic vaccines will be a good bet. ciao.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: wherehope on May 19, 2012, 08:00:01 pm
are you referring to zin finger? I wonder the modified T cells would die after a "short" period and would not multiplying. so how to cure?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: younghopefulpoz on May 19, 2012, 08:42:36 pm
Why not just try to replicate the case of Berlin patient, it'll just be like treating leukemia. I wonder why they won't offer it to patients who can afford it. Now that it's been publicly announced that HIV is not incurable but a CURABLE. Big pharmas profit will end as soon as cure will be available.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Miss Philicia on May 19, 2012, 09:04:28 pm
I wonder why they won't offer it to patients who can afford it.

Because they want you to suffer for your sins.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: wherehope on May 19, 2012, 09:42:00 pm
what sins? mistake is not sin!If it is, everybody has sins.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: wherehope on May 19, 2012, 09:47:24 pm
I think the Berlin patient is a very rare case, the procedure is risky, and also it is hard to find the exact donor, maybe that is the reason they would not replicate it. Don't know when or ever there will be a cure, but let's hope. I read an article recently which said that possibly after 10 years around there will be a functional cure but eradication is longer.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: younghopefulpoz on May 20, 2012, 01:13:19 am
They're not God to decide for us to suffer. Everybody got their own sins.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on May 20, 2012, 07:14:13 am
I think the Berlin patient is a very rare case, the procedure is risky, and also it is hard to find the exact donor, maybe that is the reason they would not replicate it. Don't know when or ever there will be a cure, but let's hope. I read an article recently which said that possibly after 10 years around there will be a functional cure but eradication is longer.

I think the study that came out a few weeks ago where scientist modified STEM cells into attacking and killing cells infected with HIV makes me think that even eradication is "just around the córner." As I'm writting this those same scientist are trying to make these cells even more potent and HIV trigger happy...Is'nt eradication of HIV infected cells in latency and HIV reservoirs the final piece of this puzzle in terms of a cure? If these cells can truly attack HIV EVERYWHERE in our bodies then we have a winner. Ciao.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: younghopefulpoz on May 20, 2012, 11:46:23 am
Yeah...
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: wherehope on May 20, 2012, 07:37:18 pm
Yeah...
Isn't it still in a mouse trial and find decreased hiv level? Hope they would go into human clinical trial next.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: wherehope on May 20, 2012, 07:37:51 pm
I think the study that came out a few weeks ago where scientist modified STEM cells into attacking and killing cells infected with HIV makes me think that even eradication is "just around the córner." As I'm writting this those same scientist are trying to make these cells even more potent and HIV trigger happy...Is'nt eradication of HIV infected cells in latency and HIV reservoirs the final piece of this puzzle in terms of a cure? If these cells can truly attack HIV EVERYWHERE in our bodies then we have a winner. Ciao.
Isn't it still in a mouse trial and find decreased hiv level? Hope they would go into human clinical trial next.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on May 20, 2012, 09:15:10 pm
Because they want you to suffer for your sins.

evil doers must be punished.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on May 21, 2012, 12:28:00 pm
I went in to get screened for both the Sangamo trials.  I wasn't a heterozygote -- so I wasn't eligible for the first trial.  But I held out hope for the second trial.  But I learned last week I'm not eligible for that one either.  Seems that my ratio (.9) was too low and my bilirubin was too high.  I found this a little frustrating -- they are looking for a ratio of 1 or above, which is a high bar and also I'm taking Reyataz so of course my bilirubin is high.  Duh!  Don't know why they put me through the whole process in the first place -- I could have told them that from the getgo.

It seems to me that in an effort to replicate the "Trenton" patient (the hetero who went UD) they are really trying to cherry pick who gets in the trials.  I suppose that makes sense.

I'm also being screened for the CalImmune trial, which should happen sometime this summer.  It's a stem cell treatment.  It's hard to find many articles on CalImmune. 

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on May 21, 2012, 04:38:33 pm
Hi geobee: new to this. 1) What do you mean by ratio? Cd4/cd8?
  2) I see much more potential in Callimmune with their RNAi than Sangamo and their zinc.
Ciao and thanks

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on May 21, 2012, 06:20:24 pm
Hey Tadeys,

Yes, the CD4/CD8 ratio.  At .9, I was doing pretty good...but not good enough.  They are looking for 1 or above (which is in the normal range I think).

CalImmune does look good.  But everything looks good from far away.  I know there are going to be three cohorts -- no chemo, mild chemo, moderate chemo.  The more chemo, the more the uptake of the new stem cells.  I should know more in a couple of months or so as I get closer to the screening.  I'm doing well on my meds, a little on the fence about partaking in CalImmune study if it's offered to me.

George
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on May 22, 2012, 11:28:00 am
While I'm certainly not in a position to compare the science of the two companies, the sheer scientific firepower of Calimmune (www.calimmune.com) which has Nobel Laureate Dr. David Baltimore as it's Board Chairman and co-founder, is impressive.

A new day is dawning.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on May 30, 2012, 10:19:53 am
http://www.modernluxury.com/san-francisco/story/the-face-of-the-cure

Decent article, particularly for those new to this approach.  For my money the most interesting quote is on page 3 (bold mine):

I think we’ll totally be able to cure HIV in a sophisticated first-world setting,” says Paula Cannon, an associate professor of molecular microbiology and immunology at USC. “It’s going to take time and money, and a big challenge is going to be how to apply the cure broadly so it’s not just an expensive boutique treatment but one that can be mass-produced.”

Huh.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on June 06, 2012, 10:54:07 am
http://the-scientist.com/2012/06/01/targeting-dna

I ♥ Gene Therapy

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: younghopefulpoz on June 06, 2012, 12:53:27 pm
promising :), thanks freewillie99 for the link.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on June 18, 2012, 07:51:54 pm
Grassy knoll territory:

This week will be 12 weeks since the first 4 heterozygote participants in the latest Phase II Sangamo zinc finger trial stopped their medications after the modified CCR5 infusions. The Trenton patient (the heterozygote who went non detectable while off meds in the first Phase I trial) went non detectable after an 11 weeks treatment interruption.

Since late last week the stock has risen approximately 15% or so on very high volume with no news.  None.  Hmmmm.

Just sayin. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Rev. Moon on June 18, 2012, 09:11:16 pm
Grassy knoll territory:

This week will be 12 weeks since the first 4 heterozygote participants in the latest Phase II Sangamo zinc finger trial stopped their medications after the modified CCR5 infusions. The Trenton patient (the heterozygote who went non detectable while off meds in the first Phase I trial) went non detectable after an 11 weeks treatment interruption.

Since late last week the stock has risen approximately 15% or so on very high volume with no news.  None.  Hmmmm.

Just sayin.

It's teh cure, Willie!!  Let us party!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on June 18, 2012, 09:22:17 pm
It's teh cure, Willie!!  Let us party!

Lol...one of these days, my friend...one of these days.


Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Solo_LTSurvivor on June 18, 2012, 09:59:03 pm
It's teh cure, Willie!!  Let us party!

Be careful or you just might have a myocardial infarction.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: alexjones on June 18, 2012, 10:33:43 pm
Oh boy, hopefully big news expected!!!! :D :D
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Rev. Moon on June 18, 2012, 10:40:01 pm
Be careful or you just might have a myocardial infarction.


OEMGEE, my left nipple is itchy.  Do you think that's a bad sign?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: LM on June 18, 2012, 10:42:45 pm
I'm a bit confused. I read this article and it says Sangamo will begin human trials only in 2014... and I'm like... wha??

Are they talking about different things or what? Here's the article: http://www.sacbee.com/2012/06/17/4565860/hiv-cure-in-works-but-issue-is.html (http://www.sacbee.com/2012/06/17/4565860/hiv-cure-in-works-but-issue-is.html)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on June 18, 2012, 11:00:59 pm
I'm a bit confused. I read this article and it says Sangamo will begin human trials only in 2014... and I'm like... wha??

Are they talking about different things or what? Here's the article: http://www.sacbee.com/2012/06/17/4565860/hiv-cure-in-works-but-issue-is.html (http://www.sacbee.com/2012/06/17/4565860/hiv-cure-in-works-but-issue-is.html)

Ya, it's different.  The current Sangamo trial is testing if they can remove cd4 cells and modify them to make the person resistant to HIV (no one thinks this will work and hasn't as of yet).

The study they are talking about in the article is to do basically the same thing except using stem cells instead of cd4 cells.  That testing won't start for a few more years and even if it is successfull will take at least a decade or two to complete.


So really no need to get all worked up about some treatment that is two decades away. 

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on June 18, 2012, 11:25:40 pm
Ya, it's different.  The current Sangamo trial is testing if they can remove cd4 cells and modify them to make the person resistant to HIV (no one thinks this will work and hasn't as of yet).

The study they are talking about in the article is to do basically the same thing except using stem cells instead of cd4 cells.  That testing won't start for a few more years and even if it is successfull will take at least a decade or two to complete.

So really no need to get all worked up about some treatment that is two decades away.

Tell that to the Trenton patient. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on June 18, 2012, 11:39:16 pm
The Trenton patient (a heterozygote) went undetectable at 11 weeks with one infusion of Sangamo-modified T-Cells.  Unfortunately his test results came back after week 12, when the trial ended.  He went back on meds without knowing he was undetectable.

As we've talked about here, Sangamo is trying to replicate the Trenton patient's experience in the current trial with heterozygotes.  Someone knows if this is working or not -- they've been off meds now for at least 12 weeks.  The second trial is for non-heteros, with a dose of Cytoxan which will suppress your own T-Cells to create "space" for the modified one.  Again, someone knows if this is working or not -- since it's been several months since the first patients were infused.

I wanted to participate, but a) I'm not a hetero and b) my numbers weren't good enough for the second trial (even though they were pretty good).  Perhaps they are cherry-picking patients to try to get the best possible outcomes.  Or they weren't getting the results they wanted so they changed the criteria -- I don't know.

If the T-Cells work great!  But as a "Plan B", I think the stem cell treatment will work.  If it's in trials in 2014 I'd say that's pretty  fast.  CIRM (the CA-based publicly funded stem cell agency) needs a "win" to justify the public money being spent.    Also, CalImmune is working on a stem cell trial -- I'm being screened for that one, too. That one takes place this summer.

PS -- Sangamo (SGMO) is a volatile biotech stock.  After being down 57% last year (due to a failure of a diabetic neuropathy trial) it's up 92% this year.  It's leading product is the HIV T-Cell treatment that I've been talking about)  Hmmmm.....

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: xman on June 19, 2012, 01:23:20 pm
Ya, it's different.  The current Sangamo trial is testing if they can remove cd4 cells and modify them to make the person resistant to HIV (no one thinks this will work and hasn't as of yet).

The study they are talking about in the article is to do basically the same thing except using stem cells instead of cd4 cells.  That testing won't start for a few more years and even if it is successfull will take at least a decade or two to complete.


So really no need to get all worked up about some treatment that is two decades away.

i think it will take less to find a functional cure. total eradication might be more difficult but with a combination of therapeutic vaccines and drugs able to reverse latency it is possible to kill definitely the virus without a stem cell transplant.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on June 19, 2012, 01:29:15 pm
i don't think it will take 2 decades, at least for a functional cure. total eradication might be more difficult but with a combination of therapeutic vaccines and drugs able to reverse latency it is possible to kill definitely the virus without a stem cell transplant.

That's not the point of this thread or the specific post I was replying to. 

We were speaking a the Sangamo stem cell trials, which yes can take up to two decades.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: xman on June 19, 2012, 01:41:46 pm
That's not the point of this thread or the specific post I was replying to. 

We were speaking a the Sangamo stem cell trials, which yes can take up to two decades.

ok, sorry. what i mean is if there's something else why continue on stem cells? we don't even know if hsc are infected by the virus. according to a recent study they are not.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: LM on June 19, 2012, 01:58:38 pm
I'm happy with waiting, as long as it works. Let's all be healthy till then.  :)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on June 19, 2012, 02:32:30 pm
ok, sorry. what i mean is if there's something else why continue on stem cells? we don't even know if hsc are infected by the virus. according to a recent study they are not.

Well, the thing about HSC is they Turn into cd4 cells.  If the are programmed to be without the ccr5 gene then you would have an ongoing and lifetime supply of cd4 cells resistant to HIV. 

The current trials that they are doing, removing cd4 cells and deleting the gene, theoretically would only work on the cd4 cells you treat.  The other cells your body makes would still be able to be infected with HIV, that's why changing stem cells seems like a more viable option.

Now, stem cell therapy is a new science (relatively) and deleting genes from stem cells is very new.  You can bet your last dollar that the FDA is going to make sure that 1. It works and 2. There are no unintended consequences before the approve the therapy.  Especially since HIv can be controlled currently using antiretroviral drugs. 

That's why I say, and that article someone posted earlier said, it will be decades before this therapy pans out.

Vaccines and eradication trials, that's a completely different set of circumstances.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on June 19, 2012, 03:12:33 pm
it will be decades before this therapy pans out.

Better call Sangamo and Callimune and tell them to save their money.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on July 01, 2012, 02:18:47 pm
Cue angst:

http://medicalxpress.com/news/2012-07-scientists-alternative-gene-therapy-technique.html

Scientists develop alternative to gene therapy: The technique points to safer, simpler potential HIV treatment

July 1, 2012 in Medical research

Scientists at The Scripps Research Institute have discovered a surprisingly simple and safe method to disrupt specific genes within cells. The scientists highlighted the medical potential of the new technique by demonstrating its use as a safer alternative to an experimental gene therapy against HIV infection.

"We showed that we can modify the genomes of cells without the troubles that have long been linked to traditional gene therapy techniques," said the study's senior author Carlos F. Barbas III, who is the Janet and Keith Kellogg II Professor of Molecular Biology and Chemistry at The Scripps Research Institute.

The new technique, reported in Nature Methods on July 1, 2012, employs zinc finger nuclease (ZFN) proteins, which can bind and cut DNA at precisely defined locations in the genome. ZFNs are coming into widespread use in scientific experiments and potential disease treatments, but typically are delivered into cells using potentially risky gene therapy methods.

The Scripps Research scientists simply added ZFN proteins directly to cells in a lab dish and found that the proteins crossed into the cells and performed their gene-cutting functions with high efficiency and minimal collateral damage.

"This work removes a major bottleneck in the efficient use of ZFN proteins as a gene therapy tool in humans," said Michael K. Reddy, who oversees transcription mechanism grants at the National Institutes of Health's (NIH) National Institute of General Medical Sciences, which helped fund the work, along with an NIH Director's Pioneer Award. "The directness of Dr. Barbas's approach of 'simply' testing the notion that ZFNs could possess an intrinsic cell-penetrating ability is a testament to his highly creative nature and further validates his selection as a 2010 recipient of an NIH Director's Pioneer Award."

Questioning Assumptions

ZFNs, invented in the mid-1990s, are artificial constructs made of two types of protein: a "zinc-finger" structure that can be designed to bind to a specific short DNA sequence, and a nuclease enzyme that will cut DNA at that binding site in a way that cells can't repair easily. The original technology to make designer zinc finger proteins that are used to direct nucleases to their target genes was first invented by Barbas in the early 1990s.

Scientists had assumed that ZFN proteins cannot cross cell membranes, so the standard ZFN delivery method has been a gene-therapy technique employing a relatively harmless virus to carry a designer ZFN gene into cells. Once inside, the ZFN gene starts producing ZFN proteins, which seek and destroy their target gene within the cellular DNA.

One risk of the gene-therapy approach is that viral DNA—even if the virus is not a retrovirus—may end up being incorporated randomly into cellular DNA, disrupting a valuable gene such as a tumor-suppressor gene. Another risk with this delivery method is that ZFN genes will end up producing too many ZFN proteins, resulting in a high number of "off-target" DNA cuts. "The viral delivery approach involves a lot of off-target damage," said Barbas.

In the new study, Barbas and his colleagues set out to find a safer ZFN delivery method that didn't involve the introduction of viruses or other genetic material into cells. They experimented initially with ZFN proteins that carry extra protein segments to help them penetrate cell membranes, but found these modified ZFNs hard to produce in useful quantities. Eventually, the scientists recognized that the zinc-finger segments of ordinary ZFNs have properties that might enable the proteins to get through cell membranes on their own.

"We tried working with unmodified ZFNs, and lo and behold, they were easy to produce and entered cells quite efficiently," Barbas said.

New Strategy Against HIV

Next, the team showed how the new technique could be used in a ZFN-based strategy against HIV infection.

The AIDS-causing retrovirus normally infects T cells via a T cell surface receptor called CCR5, and removing this receptor makes T cells highly resistant to HIV infection. In 2006, an HIV patient in Berlin lost all signs of infection soon after receiving a bone marrow transplant to treat his leukemia from a donor with a CCR5 gene variant that results in low expression of the receptor. Disrupting the CCR5 gene in T cells with a ZFN-based therapy might be able to reproduce this dramatic effect.

"The idea is to protect some of the patient's T cells from HIV, so that the immune system remains strong enough ultimately to wipe out the infection," said Barbas.
A gene therapy that uses ZFNs to disrupt CCR5 genes in T cells and reinfuses the modified T cells into patients is currently in clinical trials. Barbas and his team showed that they could achieve the same effect with their simpler ZFN-delivery method. They added ZFN proteins directly to human T cells in a culture dish and found that within hours, a significant fraction of the ZFN-treated cells showed sharp reductions in CCR5 gene activity.

After several applications of ZFNs, aided by a special cooling method that improves the ability of the proteins to get across cell membranes, the scientists were able to inactivate CCR5 genes with an efficiency approximating that of the gene therapy-based approach, Barbas said.

The new approach also appeared to be safer. A DNA-based method the team used for comparison or the viral-based methods reported in the literature by others ended up producing ZFNs for up to several days, causing a significant amount of off-target DNA damage. But the directly delivered ZFN proteins remained intact within cells for only a few hours, causing minimal off-target damage.

"At some off-target locations where the gene therapy approach frequently causes damage, we saw no damage at all from this new technique," said Barbas.

Hope for 'Tiny Factories' of Health

The team tested its direct ZFN-delivery technique with a variety of other cell types and found that it works with particularly high efficiency in human skin "fibroblast" cells. Researchers now are working on advanced therapies in which they harvest such fibroblasts from patients and reprogram the cells' gene-expression patterns so that they effectively become stem cells. These induced stem cells can then be modified using ZFNs and other genome-editing techniques. When reinfused into a patient, they can produce millions of therapeutic progeny cells over long periods.

Such techniques may one day be used to treat a vast array of diseases. Barbas, who has been developing anti-CCR5 strategies for more than a decade, wants to start with a ZFN-based therapy that disrupts the CCR5 gene in hematopoietic stem cells. These blood-cell-making stem cells, reinfused into an HIV patient, would become tiny factories for producing HIV-resistant T cells.

"Even a small number of stem cells that carry this HIV-resistance feature could end up completely replacing a patient's original and vulnerable T cell population," he said.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on July 02, 2012, 11:28:25 am
Thank you for posting this article.

What fascinating science this is -- short lived proteins that change your DNA and make your cells resistant to HIV?  Wow. 

[Changed Below]

I've been thinking a lot about this approach vs. the viral vector approach.  This approach has many advantages --

-- It's a modification of stem cells, not T-Cells
-- Fewer off target effects
-- It's relatively easy to transform skin cells to stem cells
-- It's a relatively easy (apparently) to make the stem cells immune to HIV
-- Just a small pool of modified stem cells is all you made need
-- No need to worry about ABs to the viral vector
-- You could repeat the process (vectors make ABs which take time to disappear)

I was getting a little discouraged about the T-Cell approach and have read a few things that hinted that it was difficult to work with stem cells.  So I was souring on the whole ZFN idea. But this latest development is a wow! that could, IMHO, lead to a functional cure. 



Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: anonomous on July 12, 2012, 09:39:38 am
Hi To all

Is this for real or is it like all the other so called cures? I dont know what to believe there are so many stories but with no potential hope behind them,we all have this virus that threatens our lives everyday and all we are getting is false media and hope that never seems to come.

Please can someone tell me if this is for real im tired of false hope and living with this damn virus i just want to be normal again is that so much to ask lol.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on July 12, 2012, 10:32:12 am
I think this is for real but it could be years before we see it in the clinic.   For myself, I act as if I'll have HIV forever.  A cure may come along, but I'm sure going to take care of myself (take my meds, see the doc, exercise, etc.) in the meantime.

I just listened to the Sangamo investor call.  Not much news there except that there should be an update on the HIV trial at the end of July.  The CEO (Ed Lamphier) did say it was relatively easy to recruit for the trials, which I thought was interesting.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: misterprice on July 12, 2012, 11:59:32 am

 
Also, ah, That Cd4 cells die out with in an X amount of time... Nothing new. Now Stem Cells do not die out and are always multiplying. Sooooo, for a cure:  1) More is better: the more cells without the CCR5 receptor the better. Knocking-out both receptors (CCR5 and CX4) would be best. 2) Stm Cells SEEM far more superior then cd4s for a CURE. Do we need both of these for a cure of sorts? Nobody knows for sure. Scientist stopped finding HIV In Brown a few months after the transplant...but he had virtually a new immune system after the treatment. The Trenton patient went undetected with just a few percent of his CD4s being zinc fingered...:).... don't get carried away AND please incluye a link next time. :P                                                                                                                    And another thing, would'nt count  on any one technique as being capable in and of itself in getting us to a cure. A combination of Medication + gen therapy + therapeutic vaccines will be a good bet. ciao.

Yeah, knocking-out both receptors (CCR5 and CXCR4) would be the best, in order to have an impaired immune system. I hope you do realize that, in order to work, the immune system needs to be able to comunicate through chemokine signaling; therefore, both receptors are required to modulate the recruitment of human leukocytes during the inflammatory response in order to fight potential diseases.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: leatherman on July 12, 2012, 01:15:20 pm
Please can someone tell me if this is for real im tired of false hope and living with this damn virus i just want to be normal again is that so much to ask lol.
a couple* of thoughts
(that's a Southern "couple" which means more than 1 and not necessarily 2 ROFL)

1) this thread started just about 4 yrs ago, and seeing how far along things have moved, I would suggest that you don't hold your breath waiting for this one. ;D Oh, not that it might not turn out to be the cure, it's just that science takes a long time. HIV is a retrovirus, which was little known when the epidemic started, and science has already made HUGE leaps towards understanding this and controlling this. (Look at the amazing meds we're taking today - they're a far cry from AZT) It's just going to take a long time to find a "cure", so you'll need to learn patience - like we all have. Why, I've been waiting on a cure for 3 decades, you know, while they keep saying they'll have a cure in "10 yrs". ::) (IMHO, a vaccine will probably show up before a "cure" anyway.)

2) so few diseases/viruses have actually been cured, I'm not really certain why anyone should expect HIV, a relatively "new" disease, to be cured before things that have studied and researched for decades longer. That's not to say that we shouldn't "hope for a cure" (Hey Hopey my friend, did you see what I did there? LOL) but you're going to need to plan on how you're going to live your life for a looooong time before a cure comes along. That means dealing with meds, access to health care, possible side effects, etc, along with daily life and planning for retirement.

3)Since it's going to take some time that means you'll also need to work on having a better attitude. How are you not "normal" now? (besides, just what is "normal" anyway?) Lots of people have lots of diseases and continue to live their "normal" lives, just taking the extra measures it takes to deal with their health issues, emotional issues, handicaps, etc. (Personally, although I do deal with HIV everyday, I wouldn't say that I'm "threatened" by it. The meds I'm taking have kept it in check for many years now.) Don't let HIV have more power in your life than it deserves - that's just stigmatizing yourself. (lordy there are enough haters in the world to stigmatize you without doing it to yourself. LOL ;D)

4) Finally just because this (zinc fingers stuff) hasn't turned into the cure, doesn't mean it's a false hope. The research forum is filled with info about all sorts of ways scientists are looking for the cure. I'd like to think that at least one of them is the path to the cure. ;) As mentioned it may even take a combination of methods to create the "cure". In the meantime, the catch is you just can't hang out here, wasting away your days, hoping the next post is the post about the cure. Quite frankly, none of the science seems to be far enough along for that to even be a remote possibility. But coming to the research thread and seeing how far along each of these incredible methods is (zinc fingers, getting rid of the reservoirs, stem cell transplants, vaccines, PrEP and PEP, etc - not to mention the research of new meds and improvements to the old meds) should give you lots of hope (about better meds in the future, about a cure), things to think about, and some knowledge to use to either help fund research or to talk to your legislators about so that they can properly fund the necessary projects.

I hope what I've posted can help you can understand that, while we have to live with the virus everyday, that we're all still "normal" and that in the future,  thanks to a lot of science, there will be even better HIV meds, a vaccine and, with some luck maybe even a cure. ;)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: misterprice on July 12, 2012, 04:25:11 pm
Hi To all

Is this for real or is it like all the other so called cures? I dont know what to believe there are so many stories but with no potential hope behind them,we all have this virus that threatens our lives everyday and all we are getting is false media and hope that never seems to come.

Please can someone tell me if this is for real im tired of false hope and living with this damn virus i just want to be normal again is that so much to ask lol.

Well, the idea itself seems very dangerous to me. The CCR5 receptor regulates trafficking and effector functions in memory/effector T-lymphocytes, and it plays an essential role in the inflammatory response. Destroying the CCR5 receptor could have catastrophic consequences for the proper functioning of the immune system. In addition, this would not offer protection against X4 strains.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Dr.Strangelove on July 12, 2012, 05:25:50 pm
The 1% or so of the population that has a mutation of both their CCR5 genes seems to be doing fine without the CCR5 receptor being functional.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: misterprice on July 12, 2012, 05:41:03 pm
The 1% or so of the population that has a mutation of both their CCR5 genes seems to be doing fine without the CCR5 receptor being functional.

Yeah, they seem to be doing fine. Have a good read.

Eri, R, et al., CCR5-Delta 32 mutation is strongly associated with primary sclerosing cholangitis. Genes And Immunity 5(6):444–450, September 2004.

http://www.nature.com/gene/journal/v5/n6/full/6364113a.html

Ad I said, the CCR5 receptor plays an important role in the inflammatory process.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Skydrake on July 13, 2012, 05:37:13 am

And what about astrocytes in the brain?
The zinc theraphy aims to change the  CCR5 receptor only in lymphocytes T.
The replication in the brain will continue, even faster without antiretroviral.

http://explore.georgetown.edu/news/?ID=64534&PageTemplateID=295
http://www.hiv-reservoir.net/index.php/the-news/85-bioinformatics-and-hiv-in-the-brain.html

Most ART drugs have a certain penetration in the brain:
(http://i48.servimg.com/u/f48/17/58/76/96/penetr10.jpg)

No ART, even with no CCR5 lymphocytes, means to maximize the replication in the brain by astrocytes.
Is the target of zinc therapy to make survive hiv+ but with HIV-related dementia?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on July 13, 2012, 10:08:58 am
Is the target of zinc therapy to make survive hiv+ but with HIV-related dementia?

Yes, it's all a big conspiracy.  Sangamo's evil plan is to create an army of HIV dementia zombies that they can control to take over the world.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on July 13, 2012, 10:19:04 am
Yeah, they seem to be doing fine. Have a good read.

Then again, there's opinions like this:

"It’s highly unusual,’ says Dr. Stephen J. O’Brien of the National Institutes of Health in Washington D.C. ‘Most genes, if you knock them out, cause serious diseases like cystic fibrosis or sickle cell anemia or diabetes. But CCR5-delta32 is rather innocuous to its carriers. The reason seems to be that the normal function of CCR5 is redundant in our genes; that several other genes can perform the same function".
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: misterprice on July 13, 2012, 01:06:54 pm
Yes, it's all a big conspiracy.  Sangamo's evil plan is to create an army of HIV dementia zombies that they can control to take over the world.

Well, besides his obvious evil plan, what we are saying is that there are much, much better approaches than the Sangamo's one. At this point, you better stick to Maraviroc, at least if you experience side effects, you can just stop the therapy. However, there is no coming back from gene therapy.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: misterprice on July 13, 2012, 01:10:00 pm
Then again, there's opinions like this:

"It’s highly unusual,’ says Dr. Stephen J. O’Brien of the National Institutes of Health in Washington D.C. ‘Most genes, if you knock them out, cause serious diseases like cystic fibrosis or sickle cell anemia or diabetes. But CCR5-delta32 is rather innocuous to its carriers. The reason seems to be that the normal function of CCR5 is redundant in our genes; that several other genes can perform the same function".

Yes, opinions.

"There are in fact two things, science and opinion; the former begets knowledge, the latter ignorance." Hippocrates

We better stick to facts; therefore, we better stick to the data reported in scientific literature.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on July 13, 2012, 02:02:46 pm
ignorance

Best do some better research there, slim.  The study you cite from 2004 has been repudiated. 

You can stick to Maraviroc and pardon me if I take the word of an NIH doc over yours.  That is, unless you'd like to share your credentials with the board  :)

EDIT: 

Hmmm....here's an interesting piece of scientific literature:

http://www.ncbi.nlm.nih.gov/pubmed/16633049

"Because an intact CCR5 receptor is needed for internalization of specific pathogens and homing of memory T lymphocytes to the liver, we hypothesize that a deficient expression of this receptor resulting from the CCR5-Delta32 variant may protect against PSC."

Clown


Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ann on July 13, 2012, 03:31:32 pm

Clown


Willy, I hope you were signing your post Clown rather than calling misterprice a clown. Surely you know that name-calling isn't permitted here. Right?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on July 13, 2012, 03:57:08 pm
Willy, I hope you were signing your post Clown rather than calling misterprice a clown. Surely you know that name-calling isn't permitted here. Right?

Absolutely it was a sign-off, Ann.  After recently watching The Dark Knight again and taking inspiration from Heath Ledger's Joker, it was kind of a trial balloon, a stab at re-branding, if you will.  Never would I accuse a troll fellow poster like misterprince of being a clown.  He's obviously a fine source of expertise.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: misterprice on July 13, 2012, 04:34:41 pm
Best do some better research there, slim.  The study you cite from 2004 has been repudiated. 

Can you please provide a reliable source for this ?

Quote
You can stick to Maraviroc and pardon me if I take the word of an NIH doc over yours.That is, unless you'd like to share your credentials with the board  :)


Yes, I will stick to Maraviroc. If one day this gene therapy will be FDA approved, then I will change my mind about it. Opinions are just opinions. You should never take the opinion of someone as a fact, just because he has credentials.

Quote
EDIT: 

Hmmm....here's an interesting piece of scientific literature:

http://www.ncbi.nlm.nih.gov/pubmed/16633049

"Because an intact CCR5 receptor is needed for internalization of specific pathogens and homing of memory T lymphocytes to the liver, we hypothesize that a deficient expression of this receptor resulting from the CCR5-Delta32 variant may protect against PSC."

In this paper someone hypothesizes that a deficient expression of this receptor resulting from the CCR5-Delta32 variant may protect against PSC. This is called speculation. Yes, speculation is present in scientific literature. If you say you "hypothesize", then you are speculating, it means the data of your study do not provide enough evidence of something. However, in the study that I cited, they claim there is evidence.

"This study provides evidence for an association between PSC and the chemokine receptor family, with a significantly increased frequency of CCR5-Delta32 heterozygotes (P=0.003) and a significantly higher CCR5-Delta32 allele frequency (P=0.007) in PSC patients compared to matched controls. CCR5-Delta32 was also significantly commoner in PSC compared to a large, unselected series of patients with IBD alone (P=0.027).

http://www.nature.com/gene/journal/v5/n6/full/6364113a.html

The tone is totally different.

Quote
Clown

Yep, we all love Batman the Dark Knight  ;)





Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on July 13, 2012, 06:31:27 pm
Yep, we all love Batman the Dark Knight  ;)

Speaking of the Dark Knight (and clowns)...love this:

http://www.youtube.com/watch?feature=player_embedded&v=bdb2w1Yu97E
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: misterprice on July 13, 2012, 07:50:33 pm
Speaking of the Dark Knight (and clowns)...love this:

http://www.youtube.com/watch?feature=player_embedded&v=bdb2w1Yu97E

That was really funny :D
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Mishma on July 14, 2012, 01:59:22 pm
A common misconception made in treating any infectious disease is that a drug/treatment has to kill off ALL of the pathogens in order to be effective. The reality is that one need only tip the balance in the host's favor. Host factors/cells can then eliminate or control the infection.

Even Mr. Brown has evidence of HIV provirus in his body-thus proving the point. He doesn't have active HIV and is at this point functionally cured.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Skydrake on July 15, 2012, 06:49:46 am
Best do some better research there, slim.  The study you cite from 2004 has been repudiated. 

You can stick to Maraviroc and pardon me if I take the word of an NIH doc over yours.  That is, unless you'd like to share your credentials with the board  :)

???
About Maraviroc, there is a interesting study one month old

http://forums.poz.com/index.php?topic=43938.0
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on July 19, 2012, 08:05:09 am
http://www.npr.org/blogs/health/2012/07/18/156988650/hiv-cure-is-closer-as-patients-full-recovery-inspires-new-research?ps=sh_stcathdl

Thought this was interesting.  Most of the article linked to above is more of the same old stuff, however, about halfway through there's this:

Gregg Cassin is a human guinea pig in an experiment sponsored by Sangamo Biosciences, a California-based company. His experience provides a tantalizing clue that gene therapy against HIV might work.

Cassin thinks he got HIV in the early 1980s. He didn't start antiviral treatment until his immune cell counts plunged to near-zero. He's watched many friends get sick and die from AIDS while he's remained healthy.

Last year Cassin volunteered for the gene therapy experiment. "I wanted to get into the next exciting thing in research," he says, "and completely by accident, I found out I had one of these mutations, the CCR5 mutation."

That's the same mutation that Brown's bone marrow donor had — the genetic quirk that makes him immune to HIV. But Cassin has only one out of two possible mutations, while the Berlin patient's donor has both. So Cassin is only partly protected. But it may explain why he has survived so many years of HIV infection without treatment.

In the gene therapy trial, researchers took out some of Cassin's immune cells and treated them with a chemical called a zinc-finger protease that knocks out both CCR5 genes. Then they grew billions of these engineered cells and injected them back into Cassin.

After a few weeks, according to plan, Cassin stopped taking anti-HIV drugs. He was off therapy for several weeks. But then he panicked.

"This is the part I feel a little bit bad about, a little embarrassed about," Cassin says. "But my viral load shot up, and I got nervous. So I went back onto treatment."


He may have panicked too soon. Two weeks later, Cassin got the results of his latest blood test, which had been done just before he resumed treatment. It showed the amount of HIV in his blood had started to drop sharply, even without antiviral drugs in his system.

"My body was taking care of it," he says.


Scientists will never know whether his viral load, as it's called, would have continued to drop, as Brown's did after a similar initial spike. That will take many more patients who have more definite and lasting benefits.


This guy is a heterozygote, like the so-called "Trenton patient", who went undetectable (after an initial vl spike as well).  Not exactly sure what to make of this.  Sangamo will be coming out with trial related info at the end of August I believe.  Stay tuned.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Mishma on July 20, 2012, 06:48:41 pm
Risks abound in human trials. Promising first results and legitimate concerns but we still have phase 3 and 4 trials to come. We need the numbers to prove (or disprove) the hypothesis and prove efficacy and safety.
 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on July 26, 2012, 12:05:23 am
They announce today that the results of the current trials won't be released until next year.  WTF?  They know how well it's working -- they've got patients using it, off their meds, etc.  They know by now if their VLs are coming down.  Just let us know what's happening already.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on August 02, 2012, 12:56:32 pm
This was an interesting interview -- from student at Barbas' lab at the Scripps institute re: naked delivery of ZFNs.  Sure seems promising --

http://backstory.scienceblog.com/2012/07/20/a-gene-free-gene-therapy/
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 10, 2012, 08:13:12 pm
We've got a couple of Sangamo threads out there -- responding back on this one since it seems to have the most content.

As reported on a different thread, Sangamo released more data from their Phase I study.  They got some good press from it, the stock price went up but... and a big but... there really isn't that much new news here.  They talk about "immune reconstitution" -- meaning that your T-Cells return to a normal level.  That's fantastic.  It means that the treated HIV-resistant cells hang around and multiply.  This, though, was already known.

What is NOT known is the effect on viral load.  We won't know about this until the first half of next year when preliminary results are released from the Phase II (hetero and cytoxan/increase uptake) trials.  The best part about the news today is that, so far, things seem to be working as they expected.  Also, Sangamo has long speculated that it'll take 10-15% of your T-Cells to be immune before VL will come down.  They are gathering a lot of evidence / data to back up that claim. 

While agonizingly slow progress is being made, it *is* being made and I'm hoping for good news in 2013. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Dr.Strangelove on September 10, 2012, 09:48:30 pm
Thanks for the update.
I am always a little skeptic when it comes to research updates from pharma companies. They have a lot of pressure from investors to deliver, so whatever they say should be taken with a grain of salt.

I am also quite curious to see the effects of their therapy in VL.

You'v mentioned the thing with "15% immune T-cells = major reduction of VL" before. I find it quite counter intuitive and would love to understand what is Sangamo's reasoning behind this theory. Perhaps I just missed something. Do you happen to have a link where they talk about this? Thanks.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 11, 2012, 01:05:46 am
I'm trying to remember where I heard it -- I say "heard" it b/c I think it was during a live session either on a conference call or a video of one of the conferences.   I'll hunt around for it.

This slide show is a recap of where they are / what information has been released right now:

http://www.slideshare.net/RHMBONCO/sangamos-hiv-study-slides-dr-1-morales-borges-of-arc-091212

What I didn't get the significance of until just now was Slide 14, "Asymptomatic Rectal Inflammation".  It looks like the modified cells homed in on the rectal tissue and normalized it.   I was talking to my Dr. the other day and asked why, if I'm on meds, I still have high CD8s.  She explained that though I had no HIV in my plasma, I still had it in my tissues and this was causing inflammation.  Then I saw this slide and I realized what she was talking about.  SB728-T is reducing (eliminating?) inflammation (and presumably HIV) in the tissues.  That seems like a very significant finding to me.

I'm a computer programmer -- not a Dr.  Just trying to put the pieces together as best I can.  -- George
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Dr.Strangelove on September 11, 2012, 02:01:16 am
Thanks for the link.

Hmm, don't know about the "Asymptomatic Rectal Inflammation".

I'm a biologist but my field is not directly related to HIV or immunology.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 11, 2012, 02:23:44 am
Ah, I found a mention of the 10-15% figure.

Here's a link to the Sangamo website --

http://investor.sangamo.com/events.cfm

Click the second link on the page -- a conference call entitled "2012 PacGrow Lifesciences Management Access Conference". 

At about 10 minutes into the talk, Ed Lanphier talks about the 10-15% therapeutic window that, he says, should drive a patient to be undetectable.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Dr.Strangelove on September 11, 2012, 11:04:07 pm
Thanks. Let e know if you find more...

I'm looking forward to see their data on the effect of the viral load next year. And I wonder how often you will need to get a fresh ZFN-treated T-cell infusion to remain UD.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: NYCguy on October 09, 2012, 03:57:59 pm
I've been following Sangamo for years.. VL allso seemed to me to be conspicuously missing from the latest results.  Why aren't they at least giving a little data?  Hopefully next year we will get something significant and they will start testing the next tweak.  Anyone know if that guy who was in the study is still posting somewhere?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on October 09, 2012, 05:09:46 pm
I think you're referring to Matt Sharp.  As I understand it, he was in the first Sangamo trial.  He did seem to get a significant and permanent increase in his T-Cells.  All of these first patients had viral loads decline and then went back on meds, one (the heterozygote) went UD. 

Here's Matt Sharp:

http://www.youtube.com/watch?v=arJSYJpBvI4

The only story I've seen regarding a patient in the new trials is about  Greg Cassin.  He did undergo the STI, and it looks like his body was bringing his VL down, but then he got a little nervous about being off meds and went back on HAART.  Here's the link:

http://www.npr.org/blogs/health/2012/07/18/156988650/hiv-cure-is-closer-as-patients-full-recovery-inspires-new-research

We should know by the first half of next year the results of the new trials and whether VL's are coming down or not.  My guess (no insider knowledge) is that they'll announce preliminary results at CROI in March.

Ed Lamphier of Sangamo continues to talk about achieving a functional cure for HIV -- that's a good sign.  (Of course, he also spoke very positively about their treatment for diabetic neuropathy shortly before the disappointing results were announced).  Also, if there was someone out there on one of the trials (either the hetero trial or the cytoxan trial) who had achieved undetectability, you'd think the word would have gotten out by now.  Their stock price bumps around a lot, and is about where it was last year -- this indicates to me that little or no information (good or bad) has leaked about the trials.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on October 30, 2012, 11:45:42 pm
Here's another CCR5 knockout strategy that seems to compete with Sangamo.  From the Hutchinson center in Seattle.  They argue it's more efficient.  Here's the link:

http://pulse.seattlechildrens.org/gene-repair-breakthrough-led-by-seattle-childrens-research-institute/
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Jmarksto on October 31, 2012, 01:39:19 am
Geobee;  Thanks for the post on the Seattle Childrens research -- I think this link warrants its own thread.

I generally take these announcements with a very large grain of salt.  However, the credibility of these organizations reduces the amount of salt required.  Also, there is some irony in their lack of funding and their geographical proximity to the Gates Foundation.  They are a short city bus ride away from significant funding for HIV research. 

Lets hope they can advance this technology!

JM

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ann on October 31, 2012, 03:32:13 am

I generally take these announcements with a very large grain of salt.  However, the credibility of these organizations reduces the amount of salt required.


Me too, but the way you put this made me think of those very large blocks of salt some people put out for deer. ;)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Jmarksto on October 31, 2012, 07:27:48 pm
Me too, but the way you put this made me think of those very large blocks of salt some people put out for deer. ;)

Ahhh, a salt lick...which would be the appropriate size "grain" for the Koronis KP1461 technology.

JM
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ann on November 01, 2012, 06:40:14 am
Ahhh, a salt lick...which would be the appropriate size "grain" for the Koronis KP1461 technology.

JM

'Zactly what I was thinking! You really do need a rather large grain of salt when reading many of these cure theories. Not to say we shouldn't hope for a cure some day, but we need to be realistic about it - and keep the salt handy.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on November 06, 2012, 04:14:19 pm
So I'm being re-screened for the Sangamo trial.  I was DQ'd before because of high bilirubin (I'm on Reyataz) but, after Dr. Jay sent out an email looking for more recruits, I contacted him and they decided to re-screen me.   They're testing my T-Cells, tropism and levels of adenovirus antibodies.

Apparently it's difficult to do a tropism test on people that are undetectable (as I gratefully am) because, of course, there isn't much virus to test.  It can take 6 weeks to 2 months for the test results to be ready. 

Second, tropism with respect to this trial is important -- if you go off meds and have X4 and R5 virus then of course your viral load will go up as the Sangamo modification in this trial only affects the R5 receptor on the T-Cell.

I'm waiting for the results, will keep you all posted when they come back.

Update:  Well, I hit the "save" button here on AM and then Quest called.  Turns out my A5 titer is high -- DQ'd again.  They said that this goes up and down and they'll test again in 6 months.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Jmarksto on November 06, 2012, 07:38:03 pm
geobee;  Thanks for the update and I wish you well with retesting!

JM
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Matts on November 08, 2012, 07:42:19 pm
Good luck with this experiment:)

Maybe we all can benefit from that in 10 years.
Gero Hütter's "Berlin Patient" Timothy Brown is living without meds for 5 years, so there is a evidence that the "CCR5 thing" could work.
Let's see.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Markmt on November 13, 2012, 04:38:54 pm
Thank you for keeping us informed Geobee!! Fingers crossed for good results :)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on January 02, 2013, 04:17:49 pm
Just wanted to to post a quick note re: Sangamo. 

From reading various internet sources, I think Sangamo will have preliminary results from their two trials (the hetero trial and the cytoxan trial) at CROI 2013, which takes place March 3 through 6. 

Enrollments in both trials have gone reasonably well, so by March there should be patients who have completed both trials -- undergone the infusion and then had the structured treatment interruption.

There are so many gray areas in medicine, but this data, hopefully, will tell us if SB728 works and for whom it works.   (And by "works" I mean reduces viral loads to undetectable levels, a "functional" cure).

Sangamo's Plan B is to treat stem cells (instead of TCells).    CalImmune, which I've heard little about, also plans to modify stem cells.



Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on January 02, 2013, 06:19:07 pm
Let's hope Sangamo's "Plan B" works better than Boehners...
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Markmt on January 11, 2013, 07:15:04 am
Sangamo BioSciences’ CEO Presents at 31st Annual J.P. Morgan Healthcare 9th January 2013.

(scroll down till you get to the above title. Than read Edward Lanphier presentation where he includes HIV of course ) Nothing new said, just that it stays upbeat :)

http://www.sctpn.net/1viralvoice/author/diradiocast/
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on January 14, 2013, 04:58:02 pm
Sangamo shares up 17% today.  Haven't seen any reason for the movement but something is going on. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on January 14, 2013, 06:54:13 pm
Was going to post something about that as well.  Up 17% and over 4x average volume on no news?  HIV is their primary claim to fame?  CROI 2013 late breaker registration deadline on Weds? 

Conspiracy theories abound.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: xman on January 15, 2013, 03:25:56 pm
Sangamo BioSciences: A Potentially Revolutionary 2013

By Ivan Deryugin

In medicine, there are certain watershed moments that become an enduring part of medical history, such as the discovery of penicillin, or the eradication of smallpox. Sangamo BioSciences (SGMO) has a chance of joining the ranks of such key medical milestones, as the company is working on one of the greatest unmet needs in medicine - a functional cure for HIV and AIDS. Sangamo is set to report new clinical data regarding its development-stage HIV/AIDS treatment this year, and if all goes well, the stock will soar as the market for an effective treatment remains wide open. The company is well capitalized to continue development of its pipeline, and considering the vast market potential of its lead candidate, shares offer a quality risk/reward, even following SGMO's impressive gains in the last year. Nevertheless, a binary biotechnology event requires risk tolerance, and we include two options strategies for the risk-averse investor.

Overview

Sangamo was founded in 1995, and since inception has spent over $270 million on the development of its ZFP technology. ZFP's, known technically as zinc finger binding proteins, are proteins that recognize and bind to a person's DNA. Sangamo uses these to create ZFP transcription factors that are able to turn genes on or off. When these proteins bind to DNA, they can regulate the expression of any gene in any type of cell. In addition, Sangamo has created ZFP nucleases (also known as ZFN's) that can be used in therapeutic gene modification. Sangamo's goal is to disrupt the mechanism of HIV/AIDS (as well as other diseases), and hopefully, find a way to emerge victorious in what many see as medicine's last frontier.

Since going public in 2000, Sangamo has lost over 45% of its value, as setbacks have called into question the company's positioning and strategy. But, shares have risen around 150% in the past year, as Sangamo has renewed hopes that it can triumph in the fight against HIV/AIDS. And if all goes well in 2013, gains should continue.

SB-728-T: A New Approach to HIV/AIDs

Sangamo's lead product is SB-728-T, a ZFN-based therapy whose goal is to be a functional cure for HIV/AIDS, and not just a treatment. Before I delve into the clinical data (and the path forward) for SB-728,  a review of HIV/AIDS is in order, as SB-728 has a truly unique mechanism of action. When a person is infected with HIV, the virus destroys their immune cells, specifically their CD4+ T-cells. The HIV virus binds to the surface of CD4+ cells using the viral envelope protein gp120. Once this happens, the HIV virus fuses into its host cell via a fusion peptide, thereby allowing their cellular membranes to fuse. The HIV virus leads to a steady reduction in a patient's CD4+ T-Cells, with 200 cells per microliter being the delineating line between HIV and AIDS (500-1200 in healthy adults). SB-728 targets HIV by targeting CCR5, a co-receptor that HIV uses to enter a person's T-cells. But, if CCR5 is absent from the surface of these T-cells, the HIV virus becomes less efficient. This is where SB-728-T comes in.

It has been discovered that a small subset of the HIV patient population has a natural mutation, known as CCR5Δ32, which renders patients essentially immune to HIV (it is thought that this mutation arose during the Black Death; research has shown that the bubonic plague does not "associate" with the mutation). Studies have shown that patients who have just one allele with the CCR5Δ32 mutation saw a 2-year delay in the onset of AIDS. Sangamo's goal with SB-728 is to replicate this mutation to disrupt the CCR5 gene of HIV patients to make their immune system permanently resistant to HIV. In late 2010, doctors performed a bone marrow transplant on a patient who had both leukemia and AIDS, and saw that the patient no longer had any detectable viral loads, and no longer needed anti-retrovirals. The donor from whom the bone marrow was donated had the CCR5Δ32 mutation, and it "transferred over" to the leukemia/AIDS patient. With SB-728-T, Sangamo hopes to repeat this kind of clinical result in all HIV patients.

What Does the Clinical Data Say?

SB-728-T is currently in Phase II trials, and Sangamo expects to report preliminary data in the first half of 2013, with full data by the end of the year. Sangamo reported early data for SB-728 in March 2012 (further data was reported in September 2012, more on that a bit later). Sangamo broke this trial into 2 arms: a group of 15 patients with CD4+ T-cell counts below 500, designated as Immune Non-Responders, and a group of 6 patients with cell counts above 450, designated as Immune Responders. After a month of treatment with SB-728-T, the Immune Responders group stopped taking antiretrovirals for 12 weeks. Sangamo stated that the viral loads of these 6 patients increased initially, as expected. However, 3 of 6 patients saw a 0.8 to > 2.0-log reduction in their viral loads, and one patient's viral load dropped to undetectable levels. According to Sangamo, this patient already had a CCR5Δ32 mutation. Sangamo stated that "control of HIV-RNA (suppression of VL) correlates significantly (p < 0.05) with calculated levels of circulating CD4+ T-cells that have undergone biallelic modification (i.e. modification of both copies) of the CCR5 gene. In this trial, SB-728-T showed only minor safety concerns, with the only reported symptoms being typical of those associated with infusion injections.

Sangamo reported updated Phase I data for SB-728 at the annual ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy) in September 2012. Sangamo reported that its Phase I dose-escalation study demonstrated that SB-728-T was well-tolerated, and resulted in what the company called "significant and sustained increases in CD4+ T-cells above baseline throughout the year-long period reported in the study." The increase in CD4+ T-cells was observed with a p-value of p < 0.038. Notably, 5 of 9 patients enrolled in the study showed CD4+ T-cell counts of greater than 500 cells/mm3, which is seen in the medical community as the threshold for starting HIV patients on highly active antiretroviral therapy (also known as HAART) (while guidelines published by the NIH suggest that even patients with cell counts above 500 begin antiretroviral therapy, they do not take into account the potential use of SB-728-T, and are based on the assumption that eventually, patients with cell counts above 500 will begin to see declines). Further analysis of the data done by Sangamo showed that proliferation of SB-728-T post-infusion was "sustained over the year-long period reported in the study with median modified circulating cell numbers measured to be 2.04-fold relative to input at 7 days, 0.96-fold at 6 months and 1.15-fold at 1 year post-infusion." Sangamo's Phase I data suggests that SB-728-T has the potential to reshape the immune systems of HIV patients, and allow them to fight back against the disease.

On the company's Q3 conference call, Sangamo's executives were pressed about this data, and what it means for the way forward. Wedbush argued that the FDA may not deem the data strong enough for approval given that SB-728-T does not completely wipe out the HIV virus. Analyst Liana Moussatos asked, "Based on the Phase I data, I thought it was very interesting about the treatment resulting in kind of normalizing the immune system in HIV infected patients where the virus had destroyed part of it. Is this, I mean in your discussion with the FDA, if SB-728-T treatment just restored the immune system and, say, reduces the strange cancers that result or the infections but maybe doesn't reduce viral load to nothing. Would that still be a viable treatment that could get approved?" Sangamo CEO Edward Lanphier and Geoff Nichol, the company's Executive Vice President of Research & Development, responded that this is a "hotly contested kind of question," stating that in the HIV/AIDS market, FDA approval has historically been based on viral load, which is the focus of the company's Phase II trials for SB-728-T, and that the company's goal is to render HAART unnecessary by keeping CD4+ T-cell counts above 500.

While SB-728-T does not destroy the HIV virus in every single patient, it has shown promising results, and 2013 will offer investors 2 different catalysts that can drive shares of Sangamo higher. The market for HIV and AIDS treatments is set to reach nearly $22 billion by 2018, therefore Sangamo has a tremendous opportunity to create meaningful value for its investors, as well as offer HIV patients a new treatment option, even if it captures only a minority of the market.

Financials & Pipeline Review

Sangamo ended Q3 2012 with $75.816 million in cash & investments (per its latest 10-Q filing), and expects to end 2012 with around $75 million in cash & investments. Sangamo's operating cash burn for the first 3 quarters of 2012 totaled $8.305 million, and even if Sangamo were to burn $10 million per quarter, the company would still have nearly 2 years of capital left to finance its operations.

While Sangamo is, unsurprisingly, unprofitable, the company does generate revenue ($4.907 million in Q3 2012, up 164.24% year-over-year, and $12.723 million for the first 3 quarters of 2012, up 128.38% from the first 3 quarters of 2011). Sangamo has licensing agreements for its technology in place with Sigma-Aldrich (SIAL), Dow Chemical's (DOW) AgroScience division, and Shire (SHPG). The company's agreement with Sigma-Aldrich involves the use of ZFP technology as a research reagent, while its agreement with Dow involves the use of ZFP technology in plant research. Sangamo's agreement with Shire, struck at the beginning of 2012, is the most crucial of these 3 agreements. Under the terms, Shire paid Sangamo $13 million upfront and received an exclusive worldwide license to ZFP technology for 4 different genes, covering blood clotting Factors VII, VIII, IX, and X. Shire also received rights to 3 other gene targets. Of the 6 pipeline programs (including SB-728-T) that Sangamo is currently working on, Shire owns ZFP technology in Huntington's disease and hemophilia.

In October, Sangamo and Shire presented the first set of pre-clinical data for their experimental treatment for Huntington's disease. The disease is caused by a mutation in a person's HTT gene, which is inherited from their parents. The HTT gene is responsible for encoding a protein also known as HTT. The mutation consists of a repeated stretch of DNA, known as a "CAG repeat." Under normal circumstances, a person's HTT gene has 10-29 of these CAG repeats. Patients with Huntington's disease, however, usually have more than 39. The more CAG repeats, the earlier the onset of symptoms, which include muscle and nerve degeneration, and loss of memory and cognitive control. Patients usually die within 10-20 years of symptom onset. Preclinical testing in animals has shown that lowering levels of HTT protein can slow, and potentially reverse the progression of Huntington's disease. Sangamo's pre-clinical data showed that the production of mutated HTT messenger RNA fell by more than 90%, all while leaving normal HTT cells and RNA untouched. The company expects to see this program in clinical trials by 2015. The companies' hemophilia program is also set to move into clinical testing.

Options Strategy, Takeover Prospects, and Conclusions

For Sangamo investors, gains or losses in 2013 will be driven by new data regarding SB-728-T. Fortunately, Sangamo has listed options, and they allow more conservative investors to mitigate some risk while preserving upside potential (prices are accurate as of the close of trading on Monday, January 14).

Sangamo Options Strategies, August 17, 2013 Expiration Date

   $7 Put   $8 Put   $7 Put & $11 Call
Stock Price   $8.20   $8.20   $8.20
Cost of Protective Put   $0.95   $1.50   $0.95
Proceeds from Sale of Covered Call   N/A   N/A   -$0.50
Net Cost per Share   $9.15   $9.70   $8.65
Maximum Loss   -23.50%   -17.53%   -7.51%
Maximum Profit   N/A   N/A   +27.17%
% Change Needed to Break Even   +11.59%   +18.29%   +5.49%

The August 17 expiration date is used because it encapsulates the first half of 2013, thereby allowing Sangamo investors to be protected through the company's first data release of SB-728-T, as well as giving them a chance to hold through the second data release. Of the options strategies listed above, the purchase of an $8 put is the most sensible. It caps losses at under 18% and requires a move of under 19% to be profitable, easily doable should Sangamo report positive data for SB-728-T. However, the 3 options strategies listed assume that investors have also purchased Sangamo stock outright. There is also another options strategy that I would like to highlight: the strangle. This strangle, also utilizing the August 17 options, involves purchasing the $2 call for $6.40 (giving an entry point of $8.40 per share, just 2.44% above where Sangamo is currently trading), as well as the $7 put for $0.95. The net cost is $7.35 per strangle, and it offers a similar level of protection as the options strategy outlined above, but with a smaller capital investment.

While there has been nothing substantial in the way of takeover rumors regarding Sangamo, there is always a possibility that a deal will occur given the company's cheap valuation in relation to the market that it targets. Just as GlaxoSmithKline (NYSE:GSK) did with Human Genome Sciences, Shire could move to take full control of Sangamo's pipeline. Alternatively, Gilead Sciences (NASDAQ:GILD) could strike a deal, although it would be motivated by different reasons. Gilead has delivered enormous profits to its investors by pioneering the treatment of HIV/AIDS; since going public in 1992, Gilead has returned almost 90,000% (Gilead has also helped enhance the lives of millions of patients). However, the fact that there is no cure for HIV/AIDS, and the fact that patients need continuous antiretroviral therapy to hold it at bay means that Gilead has much more stability than its biotechnology peers. However, should Sangamo and SB-728-T remove the need for such therapy, Gilead's business could be threatened. It is not unreasonable to assume that Gilead may make an offer Sangamo cannot refuse in order to protect its business. And with a market capitalization of less than $400 million, Sangamo is digestible for Gilead, even with a size-able premium. 2013 is poised to be a revolutionary year for Sangamo BioSciences, its investors, and HIV/AIDS patients.

Source: http://seekingalpha.com/article/1112651-sangamo-biosciences-a-potentially-revolutionary-2013?source=email_rt_article_readmore

The highlighted last paragraph is a bit concerning and could mean that if a takeover takes place, we, the patients will be the losers.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on January 15, 2013, 04:20:41 pm
Up another 7% today.

Things will get really fun when Sangamo and Paula Cannon start trials with ZFN modified haematopoietic (blood) stem cells in 2014.  If I remember correctly, these will then in theory produce armies of little modified CD4 cells with no CCR5 receptor.  Oh what fun that will be.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on January 15, 2013, 05:00:21 pm
In 7 weeks at CROI we should know if SB-728 works -- whether Sangamo can get enough modified cells in you to drive the VL to be UD after the rebound from the STI. 

If they don't present VL data or say it's coming later in the year... well... I'd be tempted to cross this off of my "might be a cure" list.

They've touted (often) a durable increase in T-Cells (great!) -- but it's certainly not a functional cure.  If they can show a person/people who got the treatment, went on an STI, had an increase in VL, then a reduction to zero --well, that would be just incredible.   (I don't know why they'd even bother with the stem-cell trial at that point. )

If -- a BIG if -- it does work it'll be very interesting to know for whom it works (heterozygotes, initial T-Cells count, med regimens, etc.)  I'd also be *very* curious to know what percent of cells had to be modified to drive down the VL.

Also, it works, I think you'll hear a lot of people talking about changing the vector -- delivering the treatment through the adenovirus antibody excludes most people. And the test for it takes weeks, in which case you could have acquired it, which will render the treatment ineffective. 

If Sangamo is acquired, I don't this is necessarily a bad thing.  Generics are already threatening the profits of big pharma -- they need the next new thing.  (That's why they are looking so hard for cure drugs.)  Sangamo is a small -- they are going to need a larger company (or partnership) to help bring this to the clinic on a large scale if it works.

On a personal note, I've been poz for only 3 1/2 years and, after breathlessly searching for cure headlines for a year (OK, 2) have become much more sanguine re: "breakthrough" press releases. Still, the science behind this seems solid -- and we should know soon.   Interesting times.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Dr.Strangelove on January 16, 2013, 08:06:25 am
I completely agree with all you said.

I really hope Sangamo will finally talk about viral load this time.

And yes, it wouldn't be unusual for Sangamo to be acquired by a bigger company. This happens all the time with small companies/startups that have a promising new drug in development.

I've been poz for less than 2 years. The research that is going on is exciting but I have no illusions. A 'cure' will not arrive overnight.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Skydrake on January 16, 2013, 05:42:32 pm
I completely agree with all you said.

And yes, it wouldn't be unusual for Sangamo to be acquired by a bigger company.

Maybe, but something is happening. Today its stocks topped the lists of Biggest Percentage Price Gainers among common stocks on the Nasdaq Stock Market.

(http://www.zonebourse.com/zbcache/charts/ObjectChart.aspx?Name=10811&Type=Custom&Intraday=1&Width=600&Height=500&Cycle=DAY1&Duration=7&Render=Candle&ShowName=0&Company=4Traders_us)

Besides, tech investors are praising it:

http://seekingalpha.com/article/1112651-sangamo-biosciences-a-potentially-revolutionary-2013
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Jmarksto on January 16, 2013, 06:23:49 pm
Maybe, but something is happening. Today its stocks topped the lists of Biggest Percentage Price Gainers among common stocks on the Nasdaq Stock Market.

Besides, tech investors are praising it:

http://seekingalpha.com/article/1112651-sangamo-biosciences-a-potentially-revolutionary-2013

I would like to see this technology work as much as the rest - however, I have learned that there is very often a wide gap between stock price and achieving market potential for "early entry" companies such as biotechs, clean energy, junior mining, etc.  The stock price of these small companies is subject to being whipsawed by institutional investors that run hot and cold, other investors that "pump and dump" (which is not a sexual reference), and a broader market of smaller investors that don't understand the science or the market. 

I am with geobee - show me the data on viral load and how it applies to the market (population) as a whole. Even then we have more trials to get through which will take more time and more money.

JM
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on January 22, 2013, 07:43:52 pm
Up another 6% to a 4x year high on 3x average volume.  Still no news.

Seems like someone thinks CROI will be interesting.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: blueballs on January 25, 2013, 12:13:44 pm
Is this actually real or just another funding scam?

I stopped reading when I saw the word "AIDS virus". AIDS is not a virus, it's a syndrome even I know that and I don't work in medicine?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on January 25, 2013, 04:26:02 pm
blueballs:

A little scepticism is OK when it comes to anything that is claiming a breakthrough. But a little online research also works wounders.

Is this a funding scam? No! Is it going to work in humans IS the question. There is a strong indication that it MIGHT be a revolution in AIDS treatment. Rumors are going around that Phase II results will be given in a few weeks at CROI. Fingers crossed.

-cheers
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: skycee on January 25, 2013, 11:46:53 pm
Fingers crossed, praying and hoping for the best....
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 13, 2013, 12:30:55 pm
So Quest San Francisco called back and I'm getting re-screened for the trial.  Last time I bombed out because my adenovirus antibodies titer was too high. 

Getting tested next Thurs, if I get in (the test takes a while), I'll keep y'all posted.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on February 25, 2013, 11:46:15 pm
So I had the blood draw to test T-Cells and VL.  Have to have good CD4s and UD VL for the trial.  If that comes back with a good result, then they'll test for ABs to the A5 virus and if that goes well, they'll do a tropism test.

It's hard to obtain results with the tropism test b/c, after all, they want UD individuals -- so they have to find a minute amount, multiply it, and then test for tropism.  Also, it takes several weeks for the AB test -- if that one comes back with a low AB titer and it looks like I'm eligible, I guess I'll just try to to have less human interaction until the infusion takes place -- because if get exposed to the cold virus, develop antibodies, then the treatment won't work. 

Title: Zinc Finger Nuclease mutations
Post by: Mishma on February 27, 2013, 12:27:46 pm
I was just a little worried about "off-target" nuclease activity but not so much on-target mutations. This paper, as the title depicts, talks about the later and how this can affect this treatment modality.

Bottom line: Zinc-Finger Nuclease (and this is really what this tread shoud be called) are being used to cleave DNA at a precise location where either the CCR5 receptor is either rendered inert or in the case of the "stacking" technology, used to insert new genetic material-in addition to knocking out the CCR5 gene. Alas, this form of gene therapy is not error prone. Damn.


http://www.nature.com/nmeth/journal/v10/n3/full/nmeth.2364.html?WT.ec_id=NMETH-201303


TALENs and ZFNs are associated with different mutation signatures


Zinc-finger nucleases (ZFNs) and transcription activator–like effector nucleases (TALENs) are of great interest for genome engineering in higher eukaryotic cells and organisms1, 2, 3, 4, 5. These enzymes contain the same FokI nuclease domain and induce site-specific DNA cleavage; the repair of this broken DNA via error-prone nonhomologous end joining gives rise to small insertions and deletions at the cleavage site, often disrupting genetic information. We have observed that, despite their similarities, ZFNs and TALENs are associated with different mutation patterns. We first compared ZFN and TALEN mutation signatures reported in the literature. We calculated the frequencies of insertions, deletions and complex patterns that include both insertions and deletions at target sites in mammalian cells, mammalian and nonmammalian organisms, and plants. Our analysis included a total of 1,456 mutant sequences at 122 target sites reported in 43 independent studies (Supplementary Table 1).
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on March 06, 2013, 05:21:38 pm
Here's a summary of Sangamo's presentation today at CROI about its ZFN clinical trials.  The Phase 1 trial is showing sustained reconstitution of the immune systems of participants. 

http://www.heraldonline.com/2013/03/06/4671886/sangamo-presents-new-clinical.html

Data Demonstrate that SB-728-T Possesses Necessary Immunologic Properties to Support a 'Functional Cure' for HIV/AIDS
By Sangamo BioSciences, Inc.

RICHMOND, CALIF., MARCH 6, 2013 — /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced new data from its program to develop a 'functional cure' for  HIV/AIDS  in two presentations at the 20th Conference on Retroviruses and Opportunistic Infections (CROI), held in Atlanta from March 3 to 6, 2013.

The first presentation described data from the SB-728-T Phase 1 study (SB-728-902, Cohorts 1-3) demonstrating that SB-728-T treatment of HIV-infected subjects leads to durable reconstitution of the immune system driven by increases in total CD4+ central memory T-cells (TCM) and CCR5-protected TCM. TCM are long-lived, self-renewing cells that have the ability to remember and react against foreign antigens including HIV.  The data also showed that certain cell surface marker and gene expression profiles may predict which patients will likely respond best to SB-728-T treatment.

"These important data extend our understanding of why SB-728-T treatment improves the immune system as well as the conditions required for optimal engraftment of ZFN-modified T-cells," said Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "They confirm that SB-728-T meets the key immunologic requirements for immune reconstitution in HIV-infected individuals. In addition, analysis of cell surface marker and gene expression profiles of immune system cells in subjects who show superior responses to treatment in terms of increased T-cell counts provides us with important indicators that will aid us in the optimization of our clinical trials."

"The ability of SB-728-T to durably reconstitute the immune system in HIV-infected subjects after a single treatment has never been observed before with any other therapeutic approach," commented Rafick-Pierre Sekaly, Ph.D., Co-Director & Chief Scientific Officer, The Vaccine & Gene Therapy Institute of Florida (VGTI Florida), whose laboratory carried out the analysis. "Improvement in the overall health of the immune system of HIV-infected individuals, as demonstrated by treatment with SB-728-T, is a key step along the path to developing an immunologic approach to controlling and potentially eliminating the virus. We have analyzed the cells that constitute this unprecedented elevation of total CD4+ cell counts, extending our previous observations that the increase is primarily due to durable expansion of the central memory T-cells. Importantly, the level of ZFN-dependent CCR5 gene disruption is sustained in these cells, which is critical for the durable success of this approach."

HIV destroys the immune system by killing CD4+ T cells. The current standard of care for HIV/AIDS is daily treatment with antiretroviral therapy (ART), which suppresses viral load in the blood of most subjects but does not eliminate the reservoir of HIV-infected cells.  In addition, a significant proportion of treated HIV-infected individuals do not experience a restoration of CD4+ T-cell counts to normal levels.  SB-728-T treatment, by eliminating the co-receptor, CCR5, which is necessary for HIV entry to CD4+ cells, is designed to provide a CCR5-negative population of CD4+ T-cells that cannot be infected by HIV but are able to fight opportunistic infections and enable the immune system to control and eliminate the virus. Sangamo's clinical studies have demonstrated successful ZFN-dependent CCR5 gene modification of T-cell populations, including critical cell types such as the TCM.  Studies to date have demonstrated that engraftment of SB-728-T is safe, the modified cells are durable and demonstrate prolonged trafficking and dynamic immunological responsiveness in the gut mucosa, an important HIV reservoir.  The data presented today demonstrate that SB-728-T treatment leads to unprecedented durable increases in total CD4+ T cells that are correlated with increases in TCM and ZFN-mediated CCR5-modified TCM.

"These exciting data support our development program for SB-728-T as a potential functional cure for HIV/AIDS," stated Edward Lanphier, Sangamo's president and CEO. "We have ongoing Phase 2 clinical trials designed to build on our early studies in which we observed a significant correlation between the number of infused CD4+ T cells in which both copies of the CCR5 gene are modified, so-called biallelic modification, and reduction in viral load during a treatment interruption.  We intend to present data from these trials this year."

The first of these ongoing trials (SB-728-902 Cohort 5) evaluates the approximate doubling of bi-allelic engraftment that can be achieved in individuals that have a natural mutation of one of their CCR5 gene copies, CCR5 delta-32 heterozygotes, and seeks to confirm an observation of the occurrence of aviremia during ART treatment interruption (TI).  The second trial (SB-728-1101) examines the ability of a lymphopenic preconditioning regimen to enhance bi-allelic engraftment and reduce viral load during a TI in subjects in which CCR5 is not mutated.

Sangamo expects to present preliminary data in the first half of 2013 and the full data set from both trials by the end of 2013.

Data Summary
Abstract #126 "The Central Memory T-cell is the Critical Component for Sustained CD4+ Reconstitution in HIV Subjects Receiving ZFN CCR5 Modified CD4+ T-cells (SB-728-T)"Wednesday, March 6, 2013 HIV-infected subjects were enrolled in a Phase 1 clinical trial (SB-728-902, Cohorts 1-3) and received a single dose of SB-728-T (5 to 30 billion cells). All subjects were on ART and had stably controlled undetectable levels of HIV in their blood.

The study evaluated safety and tolerability, changes in CD4+ T-cell counts and the ratio of CD4+ to CD8+ T-cells, as well as persistence of SB-728-T in the blood and trafficking of these ZFN-modified cells into gut-associated lymph tissue.
Analysis of data from subjects in the study presented today demonstrated:
·   Treatment of HIV subjects with SB-728-T leads to both acute and long term increases in total CD4+ T-cell counts.
·   Observed level of CD4+ T-cell reconstitution is significantly greater than in previously published T-cell infusion studies without CCR5 modification.
·   Long term increases in total CD4+ T-cell counts correlate with increased TCM and increased ZFN-mediated CCR5 disrupted TCM.
·   Levels of CCR5 disrupted TCM were stable or increased over time compared to other T-cell sub-populations.
·   In addition, analysis of immune cells of treated individuals provided a specific cell-surface marker profile and "gene expression signature" that characterized individuals who showed superior responses to treatment in terms of increased CD4+ T-cell counts.

In the same oral session, data were also presented from a research stage study conducted in collaboration with scientists in the laboratory of Dr. James A. Hoxie, Professor of Medicine at the University of Pennsylvania and Director of the Penn Center for AIDS Research.

Abstract #129 "T-Cells Edited to Express CCR5 or CXCR4 Fused to the C34 Peptide from gp41 Heptad Repeat-2 Exhibit Robust Protection from Diverse HIV-1 Isolates"   Wednesday, March 6, 2013      The data demonstrate potent inhibition of HIV infection in cells expressing a chimeric protein comprising a portion of the HIV envelope fused to either the CXCR4 or CCR5 HIV co-receptors.  Scientists fused the C34 peptide from the gp41 portion of the HIV envelope to the amino terminus of either the CXCR4 (C34-X4) or CCR5 (C34-R5) proteins. Importantly, both C34-X4 and C34-R5 demonstrated potent inhibition of infection by either an X4-tropic or R5-tropic HIV-1 isolate in primary CD4+ T cells, the natural target of HIV.

Webcasts of all the presentations at CROI 2013 can be accessed via the following link:http://webcasts.retroconference.org/m/2013
About SB-728-T SB-728-T is an autologous CD4+ T-cell product in which the gene for CCR5, a co-receptor for HIV entry, is modified via ZFN-mediated genome editing to disrupt the CCR5 protein.  T-cells with a disrupted CCR5 protein are resistant to infection by the most common strain of HIV.

About Sangamo Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic® for the treatment of HIV/AIDS. Sangamo's other therapeutic programs are focused on monogenic diseases, including hemophilia, Huntington's disease and  hemoglobinopathies such as beta-thalassemia and sickle cell anemia. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs).  Engineering of ZFPs that recognize a specific DNA sequence enables the creation of sequence-specific ZFP Nucleases (ZFNs) for gene modification and ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function. Sangamo has entered into a strategic collaboration with Shire AG to develop therapeutics for hemophilia, Huntington's disease and other monogenic diseases and has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the company's website at www.sangamo.com. ZFP Therapeutic® is a registered trademark of Sangamo BioSciences, Inc.

This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references relating to research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform for the treatment of HIV/AIDS, including a potential functional cure of HIV/AIDS, the expansion of clinical studies of SB-728-T in HIV-infected individuals, expected timing for the presentation of clinical trial data and the initiation of additional preclinical and clinical studies of ZFN-gene modification. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo's SEC filings, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo BioSciences, Inc. assumes no obligation to update the forward-looking information contained in this press release.

Read more here: http://www.heraldonline.com/2013/03/06/4671886/sangamo-presents-new-clinical.html#storylink=cpy
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Jmarksto on March 06, 2013, 10:45:11 pm
Here's a summary of Sangamo's presentation today at CROI about its ZFN clinical trials.  The Phase 1 trial is showing sustained reconstitution of the immune systems of participants. 

http://www.heraldonline.com/2013/03/06/4671886/sangamo-presents-new-clinical.html

I don't see any mention of effect on viral load from the SB trials in this news release.  The Street.Com also blasts the company (see the link below) implying that they are hyping the technology to keep the stock price up. I have to imagine that if Sangamo had good data on viral load to share they would - the fact that they don't (have the data, or aren't willing to publish it) does not bode well for this technology or the stock price (even after a 7% drop today).

http://www.thestreet.com/story/11861867/1/sangamos-hiv-gene-therapy-is-a-valuation-prop-nothing-more.html

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on March 07, 2013, 01:55:31 am
But the update at CROI was about the phase 1 trial, in which people were put back on meds after a brief treatment interruption, so everyone is presumably undetectable thanks to the meds.  Thus, there is no viral load data to report.  The phase 2 trial data will be presented later this year, and that will involve indefinite treatment interruptions. 

I think this update about phase 1 is extremely exciting, and very good news for Sangamo since potentially people whose CD4's have not rebounded that well despite being on meds may be able to restore their CD4's with one round of ZFN treatment. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Markmt on March 07, 2013, 06:59:17 am
I agree with cosmicdancer here!....and for some reason the article on street.com makes taking pills for hiv a piece of cake.

"in HIV patients can take a single pill each morning and basically never have to worry about their disease getting worse. These patients will grow old and die of something else before they succumb to AIDS. That's an amazing achievement in a disease that was a certain death sentence 30 years ago."

http://www.thestreet.com/story/11861867/1/sangamos-hiv-gene-therapy-is-a-valuation-prop-nothing-more.html

I think we all know the realities to this.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on March 07, 2013, 12:13:59 pm
I was disappointed that we didn't get an announcement re: VL at CROI but, on the other hand, I still remain hopeful (but less so).  Still, it's been a slow process to recruit for the Cytoxan/SGMO trial, as I've experienced myself. 

First I was bounced for high bilirubin (crazy, since, hello, I'm on Reyataz!).
... then I was bounced for the high A5 antibody (hello, people get colds!).  Then I was bounced because my CD4/CD8 ratio wasn't good enough (close, tho).

Finally, it's been difficult to do a tropism test since they only want UD participants, and it's hard to determine tropism on something that is undetectable.

So all the screening factors mean a lot of delays.  And then there's the whole "do you take the plunge" question.  If you (or I) actually pass the screening, do you go ahead with it?  Watch your VL go up and hope it comes down by the treatment?  That's a little nervous-making.

Having said that I think about other potential cures (Bryologs, therapeutic vaccines, abzymes, treatment intensification, hairpin RNA)  and still think Sangamo (T-Cells or Stem Cells) has the best shot at curing this thing.

They've promised preliminary results on the PII data by the first half of the year.  I can wait a few more months.  And really, what choice do we have?


Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: bhanu_1002 on March 13, 2013, 11:10:53 am
Any comments on the below link

http://seekingalpha.com/article/1269121-sangamo-bioscience-the-impending-failure-in-hiv
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Matts on March 13, 2013, 04:02:57 pm
I think that the Sangamo shares a a risky investment at the moment; I would wait for more information about the trials.

Dr. Gero Hütter, made a short presentation about his Berlin-patient,CCR5 and the Sangamo and Calimmune trials. He works for Calimmune now, so I don't know how realistic his assumptions are:

http://www.isheid.com/presentations/mercredi/16-00/hutter/hutter.pdf (http://www.isheid.com/presentations/mercredi/16-00/hutter/hutter.pdf)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on March 13, 2013, 04:12:50 pm
Any comments on the below link

http://seekingalpha.com/article/1269121-sangamo-bioscience-the-impending-failure-in-hiv

Sure.  It's written by a guy with a Poly Sci degree who discloses he's short the stock (i.e. betting on it to go down).  He makes several glaring errors / assertions regarding dropping vl loads during treatment interruptions.  That alone marks him as an ill informed hack and not worth listening to.  Regardless, the proof will be in the pudding come May when they present interim Phase 2 results.  Until then, talk is cheap.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ann on March 14, 2013, 07:54:25 am
Any comments on the below link

http://seekingalpha.com/article/1269121-sangamo-bioscience-the-impending-failure-in-hiv


He makes several glaring errors / assertions regarding dropping vl loads during treatment interruptions.  That alone marks him as an ill informed hack and not worth listening to. 


Unfortunately, what FreeWilly just said there can be broadly applied to most/many hacks... er.... "journalists" ~coughcough~ who write news articles and/or press releases on anything to do with hiv/aids, both in the lamemainstream press and for online news outlets.

****

After writing the above paragraph, I went into a general discussion aimed at people who are new to reading information regarding hiv/aids on the internet. I soon realised it was a major derailment of the original intent of this thread, so I decided to take what I wrote and start a new thread with it.

My main dilemma was where to put the new thread; here or in the I Just Tested Poz forum, but I settled on starting it here, mainly because that's where a lot of our newbies with a thirst for knowledge seem to end up. I hope folks read it (and comment) and I hope it helps some people learn to more safely navigate the world of hiv/aids information vs crap (or just terribly reported) science.

Ann
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on May 15, 2013, 04:48:24 pm
RICHMOND, Calif., May 15, 2013 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today the presentation of new clinical data from its program to develop a ZFP Therapeutic® for HIV/AIDS.  The data, which demonstrate that SB-728-T treatment results in a reduction in the HIV reservoir in HIV-infected subjects, are being presented at the 16th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT).  The meeting is being held in Salt Lake City from May 15-18, 2013

HIV-infected subjects enrolled in Sangamo's ongoing SB-728-902 clinical trial (Cohorts 1-3) received a single infusion of SB-728-T which resulted in a durable increase in total CD4 T-cells driven by increased ZFN-modified CD4 central memory T-cells.  The extent of exposure of subjects to circulating zinc finger nuclease (ZFN) CCR5 protected CD4 T cells correlated with a long term decrease in the peripheral blood mononuclear cell (PBMC) HIV reservoir as measured by proviral DNA.  In addition, two of four evaluable subjects in Cohort 5 of this study showed a decrease of greater than one log in their viral load during a sixteen week treatment interruption (TI) with one of the subjects achieving a transiently undetectable viral load during the TI period. In subjects in which viral load decreased, a measureable anti-HIV response was observed, specifically a multi-functional response of CD8 T-cells to elements of HIV core proteins.
"These data are quite remarkable," commented Dale Ando , M.D., Sangamo's vice president of therapeutic development and chief medical officer. "In previous clinical studies, a decline in the HIV reservoir has never been observed in subjects on long-term anti-retroviral therapy (ART) and any increase in the levels of CD4 cells in HIV-infected subjects is often associated with a concomitant increase in the size of the reservoir.  In contrast, a single SB-728-T treatment of subjects on long-term ART produced a significant and durable improvement in CD4 count and, in the majority of subjects, a notable decrease in the HIV reservoir over time.  An observed correlation with circulating ZFN CCR5 protected CD4 cells is extremely promising."

http://www.prnewswire.com/news-releases/sangamo-biosciences-presents-clinical-data-demonstrating-hiv-reservoir-reduction-in-hiv-infected-subjects-treated-with-zfp-therapeutic-sb-728-t-207530041.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on May 15, 2013, 05:02:21 pm
during a sixteen week treatment interruption (TI) with one of the subjects achieving a transiently undetectable viral load during the TI period.

Excellent news, just what I was hoping to hear.    Should we assume the person above went back on ART instead of seeing what happens longer term?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on May 15, 2013, 05:35:08 pm
I actually did'nt expect Sangamo to do this well; but we will have to wait til the end of the year for more info--at the conference on HIV revervoirs in Miami??)

The reservoir info was good news I think.

Calimune's technology is way more sophisticated than Sangamos, So I'm thinking their's will bring better news.  ;)



Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on May 15, 2013, 05:40:11 pm
I actually did'nt expect Sangamo to do this well; but we will have to wait til the end of the year for more info--at the conference on HIV revervoirs in Miami??)

The reservoir info was good news I think.

Calimune's technology is way more sophisticated than Sangamos, So I'm thinking their's will bring better news.  ;)

I'm right there with you.   I know long time members on here have "cure" news fatigue (I don't blame them), but both studies open up a whole new level of possibilities. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on May 15, 2013, 08:19:00 pm
I pondered "transiently undetectable" several times today.  I guess it means they went undetectable and then it came back?

I sort of thought something like this would happen.  Medicine is replete with non-black-and-white outcomes.  Try.  Learn.  Modify. Try again!

So...thinking about it for a bit... I am only transiently disappointed :).  The results were good just after one infusion -- repeated infusions would be a great next step.


Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on May 15, 2013, 08:26:33 pm
I pondered "transiently undetectable" several times today.  I guess it means they went undetectable and then it came back?

I sort of thought something like this would happen.  Medicine is replete with non-black-and-white outcomes.  Try.  Learn.  Modify. Try again!

So...thinking about it for a bit... I am only transiently disappointed :).  The results were good just after one infusion -- repeated infusions would be a great next step.

I agree "Transiently undetectable" is new to me as well. 
(interesting HIV-Language Evolving stuff)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on May 15, 2013, 09:17:14 pm
Transient = Not Permanent

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JazJon on May 15, 2013, 09:24:06 pm
Transient = Not Permanent

Adjective
Lasting only for a short time; impermanent.
Noun
A person who is staying or working in a place for only a short time.
Synonyms
transitory - passing - fleeting - temporary - momentary
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Common_ground on May 16, 2013, 08:20:48 am
Ill interpret it as they use the word transient because the subject went back on ART, and the TI was scheduled for only 16 weeks, no?

So to say "permanently undetectable" , well then he had to stay of ART forever.

Just like with the Berlin Patient, some claim he shouldnt be declared cured because the virus might bounce back, even its what 6 years ago?
Transient cured maybe? lol
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ann on May 16, 2013, 08:43:12 am
Ill interpret it as they use the word transient because the subject went back on ART, and the TI was scheduled for only 16 weeks, no?


It sounds to me like he went back on ART because he experienced viral rebound. Why would he go back on meds if he had an undetectable VL? I sure wouldn't.

"Viral rebound" is what they call it when you have an undetectable *hcv viral load during - and after - hcv treatment, but the VL becomes detectable again in the weeks/months following cessation of treatment. I'm assuming the same terminology would apply here. I would think "transiently undetectable" is more or less a synonym for "experienced viral rebound". Just an edjamakated guess. ;)

It may be that some of these possible hiv cures might be similar to hcv cures in that not all patients will obtain a "sustained response" - ie a cure. Something to keep in mind, folks.

*hcv = hepatitis C, for the uninitiated. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on May 16, 2013, 11:10:31 am
That patient's viral load reached undetectable and then rebounded to low thousands, and stayed off HAART till now.

http://www.investorvillage.com/smbd.asp?mb=1933&mn=53903&pt=msg&mid=12796562

Ill interpret it as they use the word transient because the subject went back on ART, and the TI was scheduled for only 16 weeks, no?

So to say "permanently undetectable" , well then he had to stay of ART forever.

Just like with the Berlin Patient, some claim he shouldnt be declared cured because the virus might bounce back, even its what 6 years ago?
Transient cured maybe? lol
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on May 16, 2013, 11:15:03 am
Other viral load response:

http://www.investorvillage.com/smbd.asp?mb=1933&mn=53905&pt=msg&mid=12796567

http://www.investorvillage.com/smbd.asp?mb=1933&mn=53906&pt=msg&mid=12796572

http://www.investorvillage.com/smbd.asp?mb=1933&mn=53907&pt=msg&mid=12796575

http://www.investorvillage.com/smbd.asp?mb=1933&mn=53925&pt=msg&mid=12797002
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on May 16, 2013, 11:16:56 am
Effects on Reservoir

http://www.investorvillage.com/smbd.asp?mb=1933&mn=53924&pt=msg&mid=12796998
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on May 16, 2013, 12:02:23 pm
I'd grade the results a B with positive (pun intended) upside potential for a better grade when the full results are posted Q4. 

It seems there's a correlation of number of infused modified cells with efficacy which makes the patients treated later in the trial potentially quite interesting.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on May 16, 2013, 12:24:07 pm
Ill interpret it as they use the word transient because the subject went back on ART, and the TI was scheduled for only 16 weeks, no?


No.

I'd grade the results a B with positive (pun intended) upside potential for a better grade when the full results are posted Q4. 

It didn't work and your giving them a "B"?  Your an easy grader.  On what earth do you give someone a B who failed to do what they intended?

The fact that  some patients experienced a durable increase in cd4 cells is something to celebrate.  There are too many people who never experience a rebound of cd4 cells upon initiation of HAART.  That is something to post about.  However, trying to read success on viral load reduction where there wasn't much if any success seems nearsighted.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on May 16, 2013, 12:41:19 pm
No.

It didn't work and your giving them a "B"?  Your an easy grader.  On what earth do you give someone a B who failed to do what they intended?

The fact that  some patients experienced a durable increase in cd4 cells is something to celebrate.  There are too many people who never experience a rebound of cd4 cells upon initiation of HAART.  That is something to post about.  However, trying to read success on viral load reduction where there wasn't much if any success seems nearsighted.

Strongly disagree. The data shows that modified CD4 cells have antiviral effect and are able to bring the viral load to undetectable in some patients! Remember, no single HIV drug(not cocktail) can bring your viral load down to that level.

Also, this is very early in Phase 2 trial, it seems, if we have over 10% modified CD4 cells, the results will probably look quite good!!

In the end, for those patients who stayed on HAART. A single infusion leads to durable CD4 increase and even a reduction in viral reservoir in PBMC.  HAART simply can't do it! 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Dr.Strangelove on May 16, 2013, 01:40:45 pm
I agree with Bug

The CD4 part is great news but the viral load reduction is disappointing.
Only a single person went UD. It seems half of the 'evaluable subjects' didn't show any significant decrease in viral load.

Question: I'm starting to lose track with all those studies. Is this the studies where all of the test subjects have a mutation in one of their CCR5 genes? In that case the reduction in viral load with this therapy would probably even less in people where both CCR5 genes are intact.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on May 16, 2013, 02:42:32 pm
I'd like to see the results in a clincal trial were multiple infusions were given WITHOUT a vector...read a few months ago on here that scientist "poured" zinc fingers onto stem cells-- no vector used-and the % of cells modified was a lot higher compared to  adenoviral vector modified stem cells.

The head of VGTI Florida (Selazy?) seems happy with the results in terms of the reservoirs... ???

And I'd like to see gene therapy + therapeutic vaccines + the strongest anti-reservoir drugs in a clinical trial.  Just saying.  :)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: bmancanfly on May 16, 2013, 02:51:55 pm
I agree with Bug

The CD4 part is great news but the viral load reduction is disappointing.
Only a single person went UD. It seems half of the 'evaluable subjects' didn't show any significant decrease in viral load.

Question: I'm starting to lose track with all those studies. Is this the studies where all of the test subjects have a mutation in one of their CCR5 genes? In that case the reduction in viral load with this therapy would probably even less in people where both CCR5 genes are intact.

Yes the test subjects who saw the viral load reduction had the gene mutation,  which makes these already underwhelming results that much more underwhelming.

If I owned this stock,  and I don't,  I'd be selling.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Matts on May 16, 2013, 03:29:30 pm
Ok it was a failure. I don't know much much cash Sangamo has and if they can conduct further trials or will become bankrupt.
I only see a future if they concentrate on the latent cells, at least they reached a reduction of 70%- better than every HAART. I'm curious what they will do in the next years.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Miss Philicia on May 16, 2013, 03:35:58 pm
Can someone summarize? Did this five year old thread go up in flames?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on May 16, 2013, 04:12:32 pm
This is NOT a failue per se. Some participants had some positive results with just ONE infusion & with very few cells actually being modified...if I remember correctly, Sangamo's technology has only modified something like 5-6% CD4s in the past  (perhaps antibodies againts the freaking adenovirus is to blame) ...I'd like to see modification in the 30-50% range. Never had my money on Sangamo's technology, but lets just wait till the end of the year for the final results; if Sangamo can demonstrate a clear connection between % of cells modified and VL/CD4s then thats great news in a Proof-of-concept kind of way that more sophisticated technology can do the trick...technology that I believe we might have already, but we just have to wait 3-5 years to start seeing phase 1 trials.  :)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on May 16, 2013, 06:09:31 pm
The correlation is very strong.
http://www.investorvillage.com/smbd.asp?mb=1933&mn=53925&pt=msg&mid=12797002

The treatment threshold seems to be around 10%.
It would be cool if they could modify over 10% stem cell  :)

This is NOT a failue per se. Some participants had some positive results with just ONE infusion & with very few cells actually being modified...if I remember correctly, Sangamo's technology has only modified something like 5-6% CD4s in the past  (perhaps antibodies againts the freaking adenovirus is to blame) ...I'd like to see modification in the 30-50% range. Never had my money on Sangamo's technology, but lets just wait till the end of the year for the final results; if Sangamo can demonstrate a clear connection between % of cells modified and VL/CD4s then thats great news in a Proof-of-concept kind of way that more sophisticated technology can do the trick...technology that I believe we might have already, but we just have to wait 3-5 years to start seeing phase 1 trials.  :)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on May 16, 2013, 07:11:47 pm
No.

It didn't work and your giving them a "B"?  Your an easy grader.  On what earth do you give someone a B who failed to do what they intended?

The fact that  some patients experienced a durable increase in cd4 cells is something to celebrate.  There are too many people who never experience a rebound of cd4 cells upon initiation of HAART.  That is something to post about.  However, trying to read success on viral load reduction where there wasn't much if any success seems nearsighted.

What can I say?  I'm easy.


Can someone summarize? Did this five year old thread go up in flames?

No, not just yet.  Hold off on that snarkstorm for a few more months until their full Phase 2 trial results come out.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: xman on May 17, 2013, 12:34:19 pm
why you call it a failure. the studies demonstrated a reservoir reduction and some degree of vl reduction. i guess it's matter of how much cells are infused. if the modified cells exceeds 70% from the total amount the effect would be enormeous. most likely not all the cells needs to be modified to control hiv without haart.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Skydrake on May 19, 2013, 03:50:02 am

why you call it a failure. the studies demonstrated a reservoir reduction and some degree of vl reduction. i guess it's matter of how much cells are infused. if the modified cells exceeds 70% from the total amount the effect would be enormeous. most likely not all the cells needs to be modified to control hiv without haart.

Because for a patient with a VL reduction (the no. 5-04 below), we obtain three patients with a switch from R5 quasi-species to R5/X4 quasi-species (no. 5-01, 5-02 and 5-05):

(http://hivforum.info/forum/usrimgs/dora/Verso%20una%20cura/ASGCT%202013/slide-24.png)

The copresence of CD4 CCR5+ and CD4 CCR5- seems the ideal habitat to trigger the switching.

It's a complete faliture, unless Sangamo will demostrate that these three patients have been harbouring dual tropic strains even before the beginning of the trial.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on May 19, 2013, 06:08:16 am
Sky, don't understand your point here. What switching?

The Berlin patient was R5/4X.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Skydrake on May 19, 2013, 08:13:09 am
Sky, don't understand your point here. What switching?

The Berlin patient was R5/4X.

But:
1) Patients of last Sangamo  trial could not. From the data released I only see that three patients are R5/4X now, and I don't understand when they become just so that. This is a key point.

2) The Berlin patient treatment isn't a good comparison with Sangamo treatment. He recevied two chemiotherapies and two bone marrow transplants. At least last chemiotheraphy destroyed most previous immune system AND THE GRAFT REACTION DESTROYED LAST RESERVOIRS. It's a common reaction of the new immune cells, from the donor, to take place in the host and destroy previous immune cells, even taking anti-graft drugs. Not only. He recevied ART even during the first period after the transplant.

Instead in the Sangamo treatment there is no graft reaction band does nothing against X4 quasi-species, so ist's very important at least to shorten the period of coexistence of CD4 CCR5+ and CD4 CCR5-.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on May 19, 2013, 11:21:08 am
I sort of get what you mean now....sort of.

But the Berlin Patient was cured of HIV before he was cured of his leukemia. His second transplant was due to the fact that his cancer sprung back; he did'nt have any rebound by the time he underwent his second transplant...and too think of it, in his case---Only case thus far really--it was easier for the drugs/the host vs graft phenomenon to kill off ALL the virus, then to kill off ALL the cancer stem cells...

About these subjects in the trial, maybe they were R5/4X before the trial, perhaps. Maybe the modified cells killed of enough R5 virus so that the R5/4X was able to get going. Perhaps. Lets just wait for clarification.

I think Sangamo has a gene therapy zinc finger to take care of 4X. But then again, don't think Sangamo can deliver the goods they way we all want. At least not by itself, at least not with one infusion. Personally, I would'nt care of having to go and get 20 infusions over a period of a year or so if it would work...but thats me.

Other Newer gene therapy technologies in pre-clinical (not talking about Sangamo,nor Calimmune) have in mind the R5/4X equation too....the one I am talking about was posted on the forum a few months ago, and their technologies seem light-years ahead of what Sangamo has. Don't worry, we will get there. Patients. :)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on May 19, 2013, 01:50:24 pm
It is very likely before the infusion. Why?
For HIV to mutate from R5 to X4, you have to throw very strong selection pressure on it (when no or few CCR5+ CD4 left). Sangamo's method only modifies a very small portion of CD4 cell. If the virus is original R5 tropic, there is no real pressure for it to mutate to X4.

Perhaps early in the trial, they were not able to identify they are dual tropic?

Because for a patient with a VL reduction (the no. 5-04 below), we obtain three patients with a switch from R5 quasi-species to R5/X4 quasi-species (no. 5-01, 5-02 and 5-05):

(http://hivforum.info/forum/usrimgs/dora/Verso%20una%20cura/ASGCT%202013/slide-24.png)

The copresence of CD4 CCR5+ and CD4 CCR5- seems the ideal habitat to trigger the switching.

It's a complete faliture, unless Sangamo will demostrate that these three patients have been harbouring dual tropic strains even before the beginning of the trial.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Skydrake on May 19, 2013, 02:21:59 pm
It is very likely before the infusion. Why?
For HIV to mutate from R5 to X4, you have to throw very strong selection pressure on it (when no or few CCR5+ CD4 left). Sangamo's method only modifies a very small portion of CD4 cell. If the virus is original R5 tropic, there is no real pressure for it to mutate to X4.

That small portion of CD4 cells, the CCR5 receptor, is the main door to the lymphocytes, the CXCR4 si only a small back door. If you close the main door, you'll have a very strong pressure for it to mutate to X4 and use the back door.

About how quick HIV is able to mutate, even without a "pressure", read this:

It is estimated that up to 5 mutations may arise with each replication cycle. The daily production of more than a billion new virions in a typical chronically infected patient implies that the virus undergoes 10–100 million rounds of replication daily, resulting in the rapid generation of viral progeny carrying every possible mutation throughout

Source:
http://cid.oxfordjournals.org/content/56/11/1667.full
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on May 19, 2013, 04:50:14 pm
but only a small fraction of whole CD4 cell population has that door closed, while the majority are still CCR5 positive(HIV can use those that are CCR5 positive). So there is no pressure to guide mutation to use CXCR4 (The berline patient case has really big selection pressure, but it didn't happen...). But it might happen once more are more CD4 cells become CCR5 negative.

http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20445&&dp=player.jsp&e=13748&mediaType=slideVideo

at 1:57:07, a girl asked similar questions, but Carl June didn't think that would happen given the small number of cells modified.

Paula Cannon's explanations regarding the same issue:
http://www.youtube.com/watch?v=IRlvOW0rBkk
at 9:40

Also, there is a price paid for every mutation happened. the majority of mutated virus are not replication competent.

That small portion of CD4 cells, the CCR5 receptor, is the main door to the lymphocytes, the CXCR4 si only a small back door. If you close the main door, you'll have a very strong pressure for it to mutate to X4 and use the back door.

About how quick HIV is able to mutate, even without a "pressure", read this:

It is estimated that up to 5 mutations may arise with each replication cycle. The daily production of more than a billion new virions in a typical chronically infected patient implies that the virus undergoes 10–100 million rounds of replication daily, resulting in the rapid generation of viral progeny carrying every possible mutation throughout

Source:
http://cid.oxfordjournals.org/content/56/11/1667.full
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: oh-no on July 04, 2013, 09:02:30 pm
There was another similar study with HIV immune stem cells from Canada.
The method was called OZ1.

http://www.catie.ca/en/treatmentupdate/treatmentupdate-172/anti-hiv-agents/clinical-trial-gene-therapy-hiv

The scientists took cells from patients made the cells resistant to HIV and infused them back.

Results:
Four weeks after infusion, technicians detected HIV-resistant cells from blood cells in 94% of people in the OZ1 group. One year after the infusion, this figure fell to 12% and two years after the infusion it fell to 7%.
No statistical significance of viral load or cell count.

Stem cells suppose to reproduce themself and produce HIV resistant T-cells.

But the majority (90%) of stem cells sits in the marrow bone. So the marrow bone is the main producer of blood cells and lymphocytes. That is why blood infusion cant repeat the marrow bone transplantation experience of Berlin patient.

In addition to marrow bone transplantation Berlin patient is on the immune suppress medication which suppress HIV. It is more dangerous than arvt. He also developed graft-versus-host disease very strong immune reaction when donor cells attack patient's HIV infected cells.

I'm sure scientists and direction from Sangamo have basic knowledge of human immunity system, they also know about similar OZ1 trials which did not succeed. So they can predict results.

Of course this doesn't mean they should stop experiment. It is a step forward for the science and medicine. With new knowledge some day the new approach will be discovered. But not in the foreseeable future, even for those who is not infected with HIV.
That is why they do their trials so slowly. Time and loud promises brings money for them.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on July 04, 2013, 09:30:31 pm
Oh no: this is the reference to what you wrote: http://www.catie.ca/en/treatmentupdate/treatmentupdate-172/anti-hiv-agents/clinical-trial-gene-therapy-hiv

Sangamo is light years ahead of OZ1. Calimmune is even way more avanced then Sangamo. City of Hope should have something soon way more avanced then Calimmune...see a pattern? :)

Cheers

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: oh-no on July 04, 2013, 10:20:36 pm
All studies just use different methods to make cells resistant to HIV.
This goal is already archived. But this doesn't brings right result for the human body: persistent presence of modified cells, significant VL decline and cell count rise.

Canadian scientists point on future goals.
Gene therapy experiments need to find ways to do the following:
get more CD34+ stem cells to take hold in the bone marrow
prolong the life of CD4+ cells containing gene therapy
demonstrate significant anti-HIV activity (lower VL)

Stem cells multiplies and live longer in bone marrow.
So the goal is to deliver them here. Theoretically it could be the process similar to transplantation, but with autologous cells. In this case there is no need to destroy patient's own immune system with chemotherapy. First bone marrow is took from the bone than modified and than injected back. But today nobody even talk about this.

They move with little steps, when the whole picture is already visible. It is like to produce phone first with 500MB memory than 1GB than 2GB when technically it is already possible to produce phone with 2GB.


However I agree there is always should be a place for the hope.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on July 05, 2013, 03:56:58 am
Quote
All studies just use different methods to make cells resistant to HIV.
This goal is already archived. But this doesn't brings right result for the human body: persistent presence of modified cells, significant VL decline and cell count rise.

Actually the fact that different methods are used means that different outcomes can be achieved. The study referred to used RNA ribozyme to treat the stem cells. Many scientist in the field no longer believe that using a ribozyme on its own can provide the long term benefits required to produce a HIV cure. Both the Calimmune and the CoH techniques involve turning off a gene that produces the CCR5 receptor, which is essential to the entry of HIV into human cells. (CoH additionally use a ribozyme as part of their treatment.) They do this through modifying cell DNA, which means that the modification is replicated each time the cell divides. The potential is for such treatments to last a lifetime, not only halting a current infections (the virus has nowhere to go)  but also preventing future infections. 

There is still a problem of transfection (as was shown in the first CoH trial) but slowly the rate of transfection has been improving. The UC Davis team achieved twice the transfection rate in mice than the original CoH pre-clinical work. The CoH are now working on improving transfection and will conduct a Pll trail when they have completed their current investigations.

Hopefully, it won't be too long before we see some data on transfection rates from the current Calimmune trial. If enough cells can be modified, there is no reason to doubt that those treated will, at some point in the future, produce enough modified cells to rid the body of the virus.

Note: One of the patients in the CoH trail in 2010 is still producing increasing levels of the therapeutic cell even though the original transfection rate was very low. See video.  http://www.youtube.com/watch?v=9XqJyYrYgwU (http://www.youtube.com/watch?v=9XqJyYrYgwU)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on July 05, 2013, 04:11:30 am
Sorry, I forgot to mention that Geoff Symonds, one of the co-authors of the paper, worked for J&J at the time the referenced paper was produced and he is now Calimmune's Chief Scientific Officer.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: oh-no on July 05, 2013, 08:33:56 am
Actually the fact that different methods are used means that different outcomes can be achieved. The study referred to used RNA ribozyme to treat the stem cells. Many scientist in the field no longer believe that using a ribozyme on its own can provide the long term benefits required to produce a HIV cure.

Yes different methods lead to different success of viral suppression.
But I don't see how this method could effect engraftment.

Cells could be resistant to virus, but as long as they die shortly after infusion therapeutic goal its not reached.

 This is a main difficulty which need to be solved.

 For the experiment it even doesn't meter which gene those cells have as long as this gene doesn't affect proliferation.
It could be just mark. The problem is that any infused cells don't live long enough.

 As I understand this is because main proliferation and production of cells take place in the marrow bone, not in the blood.
Blood doesn't reproduce itself effectively, this is the function of marrow bone.
The majority of progenitor cells are there, so infusion always has only temporary effect no meter which genes scientists have changed.


Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on July 05, 2013, 10:24:27 am
Oh no: I think all of these companies have stem cell clinical trials coming up. This should take care of cells dying off.

There is a medication used to oust stem cells from bone-marrow. If you go onto the Calimmune thread you can read up on that. One of the patients of the callimune clinical trial commented on the said thread about the side effects of that particular drug...bone pain if I remember correctly.
 
Believe me, they have most of these things figured out.
Cheers
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on July 05, 2013, 10:37:37 am
Quote
Yes different methods lead to different success of viral suppression.
But I don't see how this method could effect engraftment.

Cells could be resistant to virus, but as long as they die shortly after infusion therapeutic goal its not reached.

Different approaches allow for different delivery/transfection vectors. The case of OZ1 the team used a retrovirus as the vector. Calimmune uses a lentiviral vector which is more efficient.

If you watched the video you will see that, in the case of the CoH trial, patients who received the treatment still have modified cells in their systems years after the  procedure. So the notion that all the modified cells die soon after being re-introduced to the patient is not correct. The researchers now need to get the transfection rate high enough for the new cells replicate in sufficient numbers to overcome the virus. This is the work that CoH is currently conducing.

The above does not mean that transfection is not an issue - it is. However, rates are improving all the time as vectors are being refined and at some point - maybe in this Calimmune trial - the rate will be sufficient for clinical success.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: oh-no on July 05, 2013, 12:19:06 pm
Tadeys, I talk about stem cells. OZ1 is the stem cell project.
Long live it its not what we can expect from T-lymphocytes.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: oh-no on July 05, 2013, 12:54:05 pm
Hoyland, is there an information about rate of modified cells which last year's after infusion?
OZ1 also last but only 7%
Does CoH methods have better results?

I suggest methods does not effect proliferation significant.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ann on July 05, 2013, 01:07:06 pm
Hi oh-no, welcome to the forums.

Don't take this the wrong way, but I have to wonder why you're so fixated on reading about a cure when you're so newly diagnosed.

I would think your time would be better spent in understanding the basics of hiv. Going by your response in the What do you think of this comment about HIV by porn actor Brent Corrigan? (http://forums.poz.com/index.php?topic=49184.msg594222#msg594222) thread, you still have a lot to learn about living with hiv.

We're glad you're here and we want you to learn about living with hiv - because that's what you need to be doing first and foremost. A cure is still a long way off.

I hope you will consider starting a thread in the I Just Tested Poz (http://forums.poz.com/index.php?board=16.0) forum where you can introduce yourself and tell us a bit more about how you're doing. For example, what are you numbers and are you on meds yet or are you considering your treatment options? (Please don't answer those questions in this thread - start one in Just Tested. Thanks.)

Ann
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on July 05, 2013, 09:29:08 pm
Oh-no, this is the paper that was published in journal Science Translational Medicine, a journal published by the American Association for the Advancement of Science, which describes the work done at the CoH.

You have to remember that this paper is now three years old and the patients referred to where treated in 2008. Yes, there was only a very low level of modified cell retained after the first four weeks but twenty four months out, low levels of cell retention were still measured. As the video says, one patient of the four treated has increasing levels of modified cells to this day.

Since 2008, improvement in engraftment techniques has been a major focus of researchers and the main reason why it has taken so long to get more clinical trials started. The current Calimmune study will give the scientific community the chance to see just how far this process has come. I believe the CoH team  are now confident that they are near to getting a clinically significant level engraftment to take place and will be in a position to enrol patients in a new trial if they getting the funding to do so.

The UC Davis team, which has pre-clinical work showing higher levels of engraftment, failed in its bid to obtain funding from the CIRM and I am not sure where this program is going.

You should watch out for a team led by Prof Ben Berkhout in the Netherlands. His team is working on a slightly different approach to Calimmune but still using viral vectors. They may be in the clinic in the next six to twelve months.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on July 05, 2013, 09:30:30 pm
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130552/ (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130552/)

Forgot the link.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: 1in1000000 on July 10, 2013, 07:29:27 pm
It seems, current genetic studies are aimed to repeat the effect of entry inhibitors.
CCR5 viruses are more common, but virus can switch to CXCR4 after one mutation.
CXCR4 is important for haematopoiesis, disruption of CXCR4 will affect human health.

My conclusions based on
HIV Medicine 2012 by Hoffmann & Rocktroh
p. 96 Entry inhibitors
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on September 10, 2013, 07:57:20 pm
late breaker at ICAAC

Functional Control of Viremia in CCR5-Δ32 Heterozygous
(Δ32HZ) HIV+ Subjects Following Adoptive Transfer of Zinc Finger
Nuclease CCR5 Modifi ed Autologous CD4 T-cells (SB-728-T)
D. Ando1
, J. Lalezari2
, G. Blick3
, J. Rodriquez4
, R. Hsu5
, T. Hawkins6
, D. Parks7
, j.
Zeidan8
, R-P. Sekaly8
, S. Deeks9
; 1
Sangamo, Richmond, CA, 2
Quest, SF, CA, 3
CC,
Norwalk, CT, 4
OCMG, NPB, CA, 5
PC, NY, NY, 6
SWC, S Fe, NM, 7
CWCR, St.
Louis, MO, 8
VGTI, PSL, FL, 9
UCSF, SF, CA
Background: Expression of CCR5 by CD4 cells is necessary for productive R5
HIV infection. Biallelic KO of CCR5 in CD4 cells by SB-728-T is enhanced in
CCR5 Δ32HZ. This study was undertaken to assess the effect of SB-728-T on
Δ32HZ, following an earlier report of a SB-728-T-treated Δ32HZ whose VL
became undetectable (UD) at the end of a treatment interruption (TI). Methods:
Ten aviremic, HIV+, Δ32HZ on stable ART with CD4 counts >500/mL were
enrolled. SB-728-T was manufactured with a mean CCR5 modifi cation of 25.5%
(range 17.4-44%). Subjects received 16.2+4.2 (mean+SD) billion total cells (range
9.0-23.5). After infusion, subjects were followed for 8 wks and then underwent a 16
week TI. Results: Median duration of follow-up for all subjects is 305 days (range
70-365). Circulating total CD4 counts increased from baseline by 1156+601 cells/
mLat D28. Estimated biallelic modifi ed CD4 cells ranged from 5 to 14% of PBMC
CD4 cells at D28. Three subjects had X4/R5 at baseline and in 2 R5 subjects, TI
was terminated early per protocol due to high initial VL. One R5 subject recently
commenced TI. Of the 4 remaining R5 subjects, 1 showed no signifi cant VL
reduction from peak during TI. One subject had a 1-log VL reduction; and another
subject showed a persistent 1-log reduction from peak with a single UD VL before
resuming HAART. Both of these subjects had increased polyfunctional GAG T
cell responses. The 4th subject has UD VL persisting for 4 weeks following an
initial peak; TI is ongoing. The two subjects with UD VL during TI had low HIV
set points (VL 3-4000 copies/mL) and proviral DNA(<100 copies/106
 PBMC by
ddPCR). Conclusions: Adoptive transfer of SB-728-T in Δ32HZ resulted in VL
reductions from peak levels during TI in 3 of 4 subjects with 2 subjects having
UD levels, persisting in one subject for 4 weeks at the time of abstract submission.
Reductions in VL were associated with low baseline HIV reservoir, low HIV
setpoint, and increases in polyfunctional GAG T-cell responses. CCR5 knockout in
CD4 T cells by biallelic ZFN-mediated CCR5 modifi cation may lead to functional
control of R5 HIV infection in a subset of CCR5 delta32 HZ individuals.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on September 10, 2013, 09:04:06 pm
Hmmmmmm......
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on September 10, 2013, 09:28:54 pm
"The 4th subject has UD VL persisting for 4 weeks following an
initial peak; TI is on going."   

Does anybody know how much a person's VL would have peaked after 4 weeks of TI under non-sangamo Treatment? Correct me if I am wrong but, does'nt VL peak to pre-Treatment levels by 8 weeks?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sfpvguy41 on September 12, 2013, 05:43:46 pm
Here's the press release.  I am trying to understand (and would love to know from others if they see it) why they believe some in this study of subjects with the Delta-32 heterozygote exhibit the ability to maintain undetectable VL and others not.

Nevertheless the ability to report they have attained viremic control in anyone is pretty amazing and I believe a big step.


http://www.heraldonline.com/2013/09/12/5203805/sangamo-biosciences-announces.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Dr.Strangelove on September 13, 2013, 08:44:44 pm
Not sure this answers your question but I think one of the reasons why some patients went UD and others did not is their initial VL:

Quote
The two subjects with UD VL during TI had low HIV set points (VL 3-4000 copies/mL)

To go undetectable starting from 4000 copies/ml is a lot easier than when your initial viral load is in the tens of thousands or hundreds of thousands.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on October 28, 2013, 08:14:48 am
Reduction of Viral Load at or Below Limit of Detection Ongoing at 14 Weeks
 
Additional Presentations of Preclinical Data at Annual Meeting of European Society of Gene and Cell Therapy (ESGCT)
 
RICHMOND, Calif., Oct. 28, 2013 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today the presentation of new data demonstrating sustained control of HIV viral load (VL) at or below the limit of detection for 14 weeks (at last measurement) in an SB-728-T- treated HIV-infected subject who was not on antiretroviral therapy (ART). The CCR5 delta-32 heterozygote subject is enrolled in Sangamo's clinical trial (SB-728-902 Cohort 5) and, as part of the clinical trial protocol, is undergoing an ART treatment interruption (TI), which is ongoing.

http://online.wsj.com/article/PR-CO-20131028-902967.html
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Skydrake on October 28, 2013, 03:38:05 pm
....new data demonstrating sustained control of HIV viral load (VL) at or below the limit of detection for 14 weeks (at last measurement) in an SB-728-T- treated HIV-infected subject who was not on antiretroviral therapy (ART). The CCR5 delta-32 heterozygote subject is enrolled in Sangamo's clinical trial (SB-728-902 Cohort 5) and, as part of the clinical trial protocol, is undergoing an ART treatment interruption (TI), which is ongoing.

Was or was not this subjet on ART?
How could be possibile to perform an ART treatment interruption in a subjet who was NOT on ART?

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: GoForIt on October 28, 2013, 03:49:52 pm
Pretty easy to understand....They are saying that this person took a TI during the phase of this study.  Not that this person NEVER took ART and is taking a TI...that doesn't make any sense....

It's nice that they did achieve UD for some weeks and all but only in 1 out of the 10 subjects? Only 6 were evaluable....and only one maintained the UD. That is not very good.  Hopefully they can learn something from this one person.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on October 28, 2013, 04:25:38 pm
Do not think its that bad if one considers that the viral load correlates with the percentage of grafted CD4s...thats what I read this morning. So it is a matter of tweaking the technology OR going through a series of more treatments/doses with the current technology. Personally, I would do the process 20 times if it got me off meds for good.

Anyways, I always had my money with Callimune's technology, not zinc fingers. I am surprised that it even worked with one person...although one cant really call it victory at 14 weeks; Id like to see this person UD for a least 52 weeks. But 14 weeks IS a good sign.

Gene therapy is the most avanced technology we have in terms of a cure now that the viral load got a lot harder to eliminate with the Shock and Kill approach.

Fingers crossed with Callimmune and City of Hope's trials...
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on December 06, 2013, 08:27:37 am
Some good news:

 http://www.prnewswire.com/news-releases/sangamo-biosciences-presents-clinical-data-from-key-sb-728-t-hiv-studies--proof-of-concept-for-ongoing-sustained-functional-control-of-hiv-viral-load-cytoxan-preconditioning-successfully-enhances-engraftment-


What's up with the new term "Funtional Control"? What happened to Funtional cure?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: bmancanfly on December 06, 2013, 08:50:48 am
that link doesn't work.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Tadeys on December 06, 2013, 09:26:50 am
I guess Im having link problems today... :P

http://www.rttnews.com/2235392/sangamo-biosciences-presents-clinical-data-from-sb-728-t-hiv-studies.aspx?type=ct
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sfpvguy41 on December 06, 2013, 02:57:13 pm
Here's how I summarize this great news on HIV: Sangamo today announced further progress from actual clinical trials on the path to a functional cure of HIV (disease controlled without needing meds).... "the data that have been generated in the course of the clinical investigation of this novel therapy on reductions in viral load and the levels of viral reservoir, as well as the increases in total CD4 cells, demonstrate that a single SB-728-T treatment has the unique ability to enable sustained immunological functional control of HIV in the absence of ART."

Essentially they have announced that by pretreating with an existing drug, Cytoxan (which knocks out CD4s), they have learned how to engraft enough modified CD4 cells to modify the immune system sufficiently in certain types of patients (CCR5 heterozygotes) so it can stave off HIV without needing meds, similar to how the Berlin patient was cured. Now they have to prove this in other cases using higher engraftments, and it will have to go through Phase 3 trials and come to market, so it's not something we'll see available for years.

There's a lot to this announcement, but it's a positive step. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dico on February 22, 2014, 06:57:49 am
This thread was very interesting. Unfortunately it wasn't updated since December. Any news about this Sangamo trial and comparison with Calimmune ?

I want to restart this topic and know your thoughts (especially Hoyland).

I think there are 2 advanced approaches (clinical trials) as of 2014 :
- Sangamo/City of Hope with ZFN and cytoxan (for both CD4 and HSC) : beginning in 2014
- Calimmune/Benitech with ddRNAi and busulfan (for both CD4 and HSC) : beginning in 2014 too (with buslfan)

Why are these approaches important ? As the vaccine approach failed during the past 30 years. There is not a single vaccine nor a drug that have cured even a single patient. So, if one of the two above approaches succeeds, we can hope to have a functional cure for a subset of patients in less than 10 years.

The subset of patients are, I think, healthy youngs with no other disease (no HBV / HCV) and treated early for at least 2 years (i.e. with the lowest viral reservoirs) and with documented low viral set points (less than 5000 copies/ml ?). This subsent of patients are clearly a minority but what is important is that afterwards, the technique can be improved to cure others (like me as I have been late diagnosed and had at the beginning a high viral set point of more than 10,000 copies/ml).

I am more optimistic with the Calimmune trial as it has shown a higher engraftment of biallelic-modified CD4 according to studies and they have cleverly added an antifusion protein (C46).

I think it is possible to combine the Calimmune/Benitech method with that of Prof Ben Berkhout (inhibiting HIV proviral replication) and with a combination of Busulfan for HSC and Cytoxan for the CD4. I think both chimio will raise the engraftment to a maximum level of one third modified cells (which is not that high unfortunately) at the beginning and maybe more afterwards as the non-modified CD4 will die with treatment interruption.

So what are your thoughts ?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on February 22, 2014, 09:35:29 pm
Dico,

There is a third trial approved but not yet recruiting.

Busulfan and Gene Therapy After Frontline Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma
http://www.clinicaltrials.gov/ct2/show/NCT01961063?term=city+AND+hope+AND+HIV&rank=3 (http://www.clinicaltrials.gov/ct2/show/NCT01961063?term=city+AND+hope+AND+HIV&rank=3)

The City of Hope clinical data from four years ago and the Sangamo clinical data are the only data available for these gene therapies in humans. The Calimmune pre-clinical data is very positive (one more pre-clinical publication to be released) but it is pre-clinical and therefore cannot be compared directly with the other two data sets. The Calimmune science looks good but, until we see some data coming out of the trail, I think it is too early to judge which of these approaches is likely to be the most efficacious.

I understand that Calimmune is already planning a second trial, which is a good sign that they are confident the results for this trial will be positive. The other thing about Calimmune is that they are not a government or educational facility nor do they have other treatments in the pipeline. Curing HIV is there entire raison d'etre. A failure for them is the end of the line and so I am sure their scientists are paddling like crazy to make Cal-1 work, or at least work out how to refine it so that it does work.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on February 22, 2014, 10:04:36 pm
I should have added that the lead scientists or CEO for all of these trials are attending this roundtable event. Dr Zaia for Sangamo/CoH, Dr deGiusto CoH and Mr Breton Calimmune.

http://www.oxbridgebiotech.com/events/gene-therapy-risky-business/ (http://www.oxbridgebiotech.com/events/gene-therapy-risky-business/)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dico on February 23, 2014, 02:21:52 am


I understand that Calimmune is already planning a second trial,

Hoyland,

Where did you find this info ?

Thanks
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on February 23, 2014, 06:05:07 am
Dico, the following has been confirmed by other sources.

Quote
The therapy is currently in a Phase I/II clinical trial in California, and Calimmune plans to expand its clinical studies to other countries, including Australia, in the near term. Therapeutic Innovation is supporting work-up for the planned Australian trial.


http://www.therapeuticinnovation.com.au/About_Us/Latest_Projects/Calimmune_patient-focused_HIV_solutions_development.aspx (http://www.therapeuticinnovation.com.au/About_Us/Latest_Projects/Calimmune_patient-focused_HIV_solutions_development.aspx)

In terms of your question above about different types of individuals that can be treated, Calimmune's own publicity says:

Quote
Calimmune is also developing a rich product candidate pipeline to address the needs of different types of individuals at different states of HIV infection and with different levels of treatment experience.

Hope this helps.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dico on February 23, 2014, 12:08:11 pm
I contacted the ANRS, the equivalent of NAID but in France.

They confirmed they plan to test an anti-hiv gene therapy. They follow closely the Calimmune trial but they think this trial lacks ambition. They don't believe in the C46 approach of Calimmune but want to add 3 anti-HIV protein RNAi.

I actually found an English article speaking about that (the other ones are in French) :

http://www.catie.ca/en/treatmentupdate/treatmentupdate-196/hiv-cure-research/promise-genetic-therapy-hiv

Quote
Led by France’s premier scientific research agency, the ANRS (Agence nationale de recherches sur le sida et les hépatites virales), researchers in France, Austria, Germany, Italy and the U.S. are planning to conduct clinical trials of a gene therapy that has the potential to interfere with key HIV proteins (called Tat, Rev and Vif) and to also block the CCR5 receptor of cells. Such a multifaceted approach carries the possibility of not only protecting cells from the entry of HIV but also helping the immune system overcome the toxic effect of HIV’s proteins.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dico on February 23, 2014, 12:18:56 pm
It would have been better if all of them : Calimmune, ANRS, Prof Ben Berkhout, etc... collaborated together. But it seems there is a competition between them.

In the mail, the researcher told me that it was very difficult to have more knowledge of the Calimmune trial. As I understand, and when we read his mail between the lines, it seems that David Baltimore and his Calimmune company don't want to cooperate and share their knowledge with others.

I would hope we had more power to force them to work together.

Nevertheless,  I will write another mail to know when they plan their clinical trial in France.
And if some other guys know more about other clinical trials being planned around the world, feel free to share it to us.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on March 05, 2014, 11:10:46 pm
Happy to see that this study is published in NEJM

http://www.nejm.org/doi/full/10.1056/NEJMoa1300662?query=featured_home

The results published are much earlier in the trial. SGMO has moved a lot forward.
This presentation makes a nice summary.
http://wsw.com/webcast/cowen16/SGMO/

In the heterozygous cohort, one patient stays undetectable without HART for more than 20 weeks and ongoing.

The company is now trying to enhance the engraftment and going to release new data at croi 2014:

Cyclophosphamide Enhances SB-728-T Engraftment To Levels Associated With HIV-RNA Control

The company is also going to start a trial middle this year using stem cells! And their new technology allows over 50% disruption of both CCR5 gene.

Looking forward to it :-)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on March 05, 2014, 11:16:32 pm
Their progress on using stem cells:

http://at.pscdn.net/008/00240/symposia/2013/paula_cannon/
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dico on March 06, 2014, 02:08:44 am


The company is also going to start a trial middle this year using stem cells! And their new technology allows over 50% disruption of both CCR5 gene.



Are you really sure about that ?? I never read any articles telling such a thing.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on March 06, 2014, 02:34:33 am
Are you really sure about that ?? I never read any articles telling such a thing.


For the stem cell trial planned in the middle of this year. look at the slides:
http://wsw.com/webcast/cowen16/SGMO/  (at the end)

New method for gene disruption using mRNA:
http://at.pscdn.net/008/00240/symposia/2013/paula_cannon/

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on March 06, 2014, 08:01:08 am
Looks like SGMO is getting a massive amount of attention based on their presentation yesterday at CROI.  The CEO talks about their HIV efforts and the stock goes up 25%.  Getting press in the New England Journal of Medicine and a feature on CBS News doesn't seem to have hurt either.  Hmmm...
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dico on March 06, 2014, 03:15:48 pm

For the stem cell trial planned in the middle of this year. look at the slides:
http://wsw.com/webcast/cowen16/SGMO/  (at the end)

New method for gene disruption using mRNA:
http://at.pscdn.net/008/00240/symposia/2013/paula_cannon/

Yes but I don't see the 50% you were talking about...
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on March 06, 2014, 03:33:22 pm
Yes but I don't see the 50% you were talking about...

It is at the end of the presentation. If you can't find it here is another presentation using the same technology. They show that it can modify up to 80% of the stem cells (7:50) at large scale, which prompts their collaboration with biogen.

http://www.youtube.com/watch?v=Md9yAYJCtpQ
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: sfpvguy41 on March 06, 2014, 10:01:38 pm
Great news from Sangamo today at CROI:

1) pretreating with Cytoxan makes their treatment more effective
2) they have achieved functional control of HIV in one individual who has gone off treatment for 31 weeks.
3) they are trying delivery via mRNA rather than using a virus, which allows for retreatment


http://online.wsj.com/article/PR-CO-20140306-911981.html

A quote:
"The achievement of over 7 months of ongoing functional control of viral load without antiretroviral therapy and the progress that we are making in understanding how to best deploy this novel therapy are very exciting, " commented Gary Blick, M.D., AAHIVS, Medical & Research Director, CIRCLE CARE Center, who presented the data at CROI and is an investigator on both studies that were reported at the meeting. "The data that have been generated over the course of the clinical investigation of SB-728-T demonstrate immune reconstitution, enhanced survival of the zinc finger nuclease-modified T-cells in the presence of the virus and associated reductions in viral load and the levels of viral reservoir, all of which are necessary to provide functional control of the virus."

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on April 13, 2014, 03:08:08 pm
Really nice article.  Informative and encouraging.

http://aumag.org/wordpress/2014/04/11/editing-genes-for-a-cure/

Editing Genes for a Cure

Posted on April 11, 2014 by A&U in LifeGuide, Treatment Horizons

A functional cure candidate modifies genes to create HIV-resistant cells
by Chael Needle

Gary Blick, MD, AAHIVS, Medical & Research Director of CIRCLE CARE Center and Chief Medical Officer of World Health Clinicians, doesn’t throw the word “cure” around lightly.  As an HIV physician for over thirty years, he remembers when researchers were buzzing about a possible HIV vaccine in 1984 (“give it ten years”) and how the horizon of expectations kept being shifted forward (“give it ten more years”) as predicted deadlines would pass without any good news (“we’re not sure when or if”).

Now, building on years of research and the momentum created by the bone-marrow stem-cell transplant that cured the Berlin Patient (Timothy Ray Brown), attention has increasingly focused on the possibility of a functional cure, the ongoing and sustained control of viral load without antiretrovirals. A functional cure would mean that antiretrovirals, which bring with them lifelong benefits as well as lifelong challenges, such as major expenditures (the U.S. government spent $27.7 billion in research, services, and treatment of HIV in 2012 alone), kidney and bone marrow toxicities and other side effects, would no longer be needed long-term. With early but significant successes, a gene-therapy product, pioneered by Sangamo Biosciences called SB-728-T, has found its footing among the nascent field of functional-cure candidates.

Dr. Blick is excited about the results from initial clinical research on SB-728-T, but his excitement is tempered with wait-and-see realism. Sharing the latest news about this new therapy, he had a busy time as a presenter at this year’s Conference on Retroviruses and Opportunistic Infections (CROI 2014). Data from a raft of SB-728-T clinical trials led by Sangamo BioSciences, and in which Dr. Blick is an investigator, shows significant viral load reduction through an intravenous infusion of billions of a patient’s own CD4+ T-helper cells, ones that have been extracted, genetically modified, and re-infused into the body.

What’s extracted? First blood is extracted and then the individual’s own CD4+ T-helper cells are separated out to be modified. CD4+ T-helper cells, much needed for immune protection, are rendered ineffective and die off as a result of HIV infection. SB-728-T infusions have shown long-term increases in CD4+ T-helper cells, which correlates with increased CD4 central memory cells and gene-modified central memory cells.

What’s modified? Using Sangamo’s proprietary genome editing technology—zinc finger nuclease, or ZFN—the extracted cells’ DNA is modified to mimic those one percent of individuals who have been found to be immune (or largely resistant) to HIV because of a natural (and apparently harmless) genetic mutation: CCR5delta32. Having CCR5delta32 results in the expression of a shortened, or truncated, and non-functional CCR5 protein, whose co-receptors are needed for HIV to gain entry into cells. Individuals who have two copies of the mutation are virtually immune, and this is one possible mechanism that has tagged some individuals as elite controllers or long-term non-progressors, meaning some are still able to be infected by HIV but also able to indefinitely control HIV with low or undetectable HIV-1 viremia without antiretrovirals.

What happens after re-infusion? Billions of cells are reintroduced and go through a process of engraftment. Researchers used one cohort to study to what extent, and at what dose, this engraftment is primed by a short-term, one-time infusion of a chemotherapeutic agent known as Cyclophosphamide, or Cytoxan (CTX).

Another cohort showed that CD4 cells can be significantly increased, viral load decreased as much as ninety-nine percent, and the ZFN-modified CD4-cell count can be increased with increasing doses of CTX therapy. Two of three subjects treated with the highest dose of CTX remain on treatment interruption for eleven and twelve weeks with stable or lowered levels of viral load.

Overall, the study showed that an individual’s T cells can be safely engineered via ZFN-based genome editing to make them HIV-resistant and safely infused, resulting in decreases in HIV viral load off antiretroviral therapy.

In another cohort discussed at CROI, one patient has shown ongoing control of viral load with nearly undetectable levels of HIV for thirty-one weeks (now thirty-five weeks as we went to press) without antiretrovirals. This patient, who looks to be on his way to a functional cure, was discovered to have one copy of the CCR5delta32 mutation and has been enrolled in a Phase II trial focused on other individuals without identical pairs of genes for the same trait (heterozygous). “We figured it would be a whole lot easier to do the gene modification if you only have one of two alleles that we needed to modify,” notes Dr. Blick. In other words, this process mimics homozygous individuals, who have two copies of the CCR5delta32 mutation. This patient at baseline had a greater percentage of T cells where both alleles were modified and fully resistant to HIV. Levels of circulating cells with biallelic modification of CCR5 may correlate with control of viral load, according to early analysis. The information will add to the bank of knowledge of how to best use this gene-modified therapy with individuals who do not carry any mutation.

Dr. Blick reports that this individual’s gene-modified T cells are also being analyzed to see if they may be hiding HIV DNA within them.

Currently the gene-modified therapy uses an adenovirus vector as a delivery system. The limitation of the adenovirus vector is that it may cause the body to produce antibodies, which ultimately can interfere with the engraftment of the associated gene-modified cells.

Thus, Sangamo is looking at other delivery systems, namely, mRNA (messenger-RNA). As RNA is a natural part of our bodies, unlike the adenovirus, explains Dr. Blick, the body will not produce any antibodies to run interference against the engraftment of the gene-modified cells and strengthen the possibility of an efficacious functional cure, as well as allow for repeated infusions, if found necessary.

The gene-modified, CCR5-disrupted cells function to not only resist infection by the most common strain of HIV but prevent its persistence.

Significantly, the modified cells have been to shown to have a longer life than the unmodified cells when exposed to HIV during a planned interruption of antiretrovirals, and, importantly, have been found to circulate where latent HIV hides out, such as gut-associated lymphoid tissue. “Lymphocytes have a normal lifespan. And T cells are lymphocytes,” reminds Dr. Blick. “So you know they’re going to have a normal lifespan, typically no greater than 120 days. If infected with HIV and not immune they’re going to die earlier than 120 days. The lifespan of the gene-modified cells—the half-life of gene-modified cells [was shown to be] something like forty-eight weeks, almost one year. We’re actually learning now that it’s going to be quite a bit longer. These gene-modified cells, for some reason, last significantly longer than if they weren’t genetically modified.”

This discovery of preferential survival has been enlightening in terms of measuring the reach of gene-modified cells. “As we’re giving 10 to 40 billion T cells, you expect to see a big bump up in the person’s CD4 cell count and then come down gradually, during treatment interruption, toward the end of treatment interruption, or if they stay on treatment interruption. But they always stayed somewhere around two to three times higher than the individual’s baseline. So, when the cells come down, where are they going?

“We know these T cells are trafficking into lymphoid tissue. These T cells are going into those reservoirs, just like the old T cells did with virus in them.” The difference here is important as antiretroviral drugs have not been shown to follow these infected cells into the reservoirs. “These gene-modified cells will not have virus in them because they’re immune and will fill up these reservoirs. We’ve demonstrated that already.”

Asked if this type of gene-modify therapy might work best in virally suppressed treatment-experienced patients, Dr. Blick responds: “At the very beginning when we started this clinical trial, about a year and a half ago, we thought a T-cell ratio, the CD4/CD8 ratio over 1 would be the parameter that would predict the best responses. We thought that an individual who was HIV-positive for less than ten years would give the best responses. We learned through the clinical trial that was not so. So now we’re treating anybody, no matter what their duration of HIV is or what their CD4/CD8 ratio is.

“But there are some exclusion criteria for these first group of patients. To get into these studies, you have to have 500 or more T cells, and you’ve got to be undetectable, because we don’t want virus replicating at the time you’re giving the gene therapy. In fact, when we give the gene therapy, we wait an additional six weeks for older T cells to die off so that the engraftment of the gene-modified T cells can take hold. And six weeks after we do the gene therapy is when they come off their medication.” As the trials are using a chemotherapeutic agent, the FDA requires other criteria to be met, as well, such as platelet counts of 200,000 and neutrophil counts of 2,500 or greater.

“We’ve been learning as we go along but so far we’ve had nothing negative to say about [the therapy],” notes Dr. Blick. Mild nausea seems to be the most severe occurrence.

Next steps in this research include the addition of a study arm to continue studying CTX dosing to achieve the best engraftment of cells (results presented were based on 1 gram/meter2; the new arm will look at 1.5); finalizing the technology for an mRNA-vector gene modification; and, once all the data from this Phase I/II study is collected about cell infusion and CTX dosing and checks out completely for safety, moving onto a Phase IIa study.

“This is really, really early data at this point,” Dr. Blick reiterates. “So, as long as everything keeps going well with this clinical trial, we have that first sign of a prolonged functional cure [in a person] now at thirty-five weeks; and now we have a second person who dropped about ninety-nine percent of his viral load, 1.9 logs. He’s still doing well. Early numbers, very few people in these Phase I clinical trials—so it’s best to say we’re cautiously optimistic.

“For me, as I’ve been doing research since 1990, understanding and uncovering all of these key findings as we go on is one of the most exciting things about doing this. We always have to give the credit to the patients for even getting involved with us and helping further the whole science of this, but just to watch this process step by step by step and learning how these things work and potentially coming up with the first functional cure for HIV is such an exciting field to be in, and such an exciting time right now.”

◊For more information about World Health Clinicians, log on to: www.worldhealthclinicians.org. For more information about Sangamo BioSciences, Inc., visit: www.sangamo.com.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: YellowFever on May 07, 2014, 09:03:20 am
I've recently learned, from watching Behind The Scene videos of Lion King, The Musical, that Rafiki (the baboon that goes naaaaa zewenya mama de chi baba) was modelled after the Sangoma in South Africa. Sangomas are faith healers/shamans/oracles that are prevalent in SA. I wonder if the name Sangamo was a play on that word...Abit off topic from OP but I cant but indulge in abit of brain tickling...
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Dr.Strangelove on May 07, 2014, 11:42:52 am
From what I understand on their 'About Us (http://www.sangamo.com/about)' section, the name is derived from Sangamon County (https://en.wikipedia.org/wiki/Sangamon_County,_Illinois), Illinois.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: YellowFever on May 07, 2014, 01:33:57 pm
*bubble bursts*....I didn't manage to read the side bar bit when I looked it up...
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on May 13, 2014, 12:55:05 pm
Quick Update:  I went back to Quest for a different study/trial and learned that Sangamo will be using a different vector for its trial this summer.  Many of us were DQ'd from the first trial because of the presence of antibodies to the adenovirus (a cold virus).  So they are using a different vector this time.

Also, they said that certain T-Cells may be better at killing of HIV.  HIV targets them first.  So if you go on meds early, you may have more HIV fighting T-Cells. 

I'm on the list for the next trial.  If I get accepted, I'll provide updates of how it goes.  I think it's supposed to open sometime this summer.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Jmarksto on May 13, 2014, 01:40:35 pm
Thanks Geobee, I appreciate the updates.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on May 14, 2014, 01:41:54 am
The new approach use MRNA for delivery, which also has a higher percentage of modification. It seems they will start a stem cell trial this summer too.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on May 26, 2014, 10:17:38 pm
Looks like Sangamo will receive another $5.6M of public funding from the CIRM to start their next Pl study.

http://www.cirm.ca.gov/sites/default/files/files/agenda/140529_AGENDA_ITEM_8_SP3_May_ICOC%20_0.pdf (http://www.cirm.ca.gov/sites/default/files/files/agenda/140529_AGENDA_ITEM_8_SP3_May_ICOC%20_0.pdf)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Matts on May 28, 2014, 05:18:35 am
Is this ZFN research similar to Sangamo?
The Aarhus University has published some papers, but I am not a ZFN expert.


"HIV can cut and paste in the human genome

Aarhus University has developed a technology that uses the HIV virus as a tool in the fight against hereditary diseases - and in the long term, against HIV infection as well. The technology repairs the genome in a new and safer manner..."

http://health.au.dk/en/#news-2163 (http://health.au.dk/en/#news-2163)

"Targeted genome editing by lentiviral protein transduction of zinc-finger and TAL-effector nucleases"
http://elifesciences.org/content/3/e01911 (http://elifesciences.org/content/3/e01911)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on June 10, 2014, 11:21:38 am
For you science nerds out there, here's a pretty detailed slide show from a few months back regarding Sangamo's upcoming Hematopoietic stem cell (HSC) trial.  It was presented at the World Stem Cell Summit last December.

http://medical.wesrch.com/paper-details/pdf-ME1XXFH5NBPBK-genome-editing-with-zinc-finger-nucleases#page1
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on June 12, 2014, 06:27:07 pm
So I'm getting screened in 2 weeks at Quest / San Francisco.

In the previous trial, you could only get one injection of the modified T-Cells since it was delivered in the cold virus.  After the first injection, your body developed ABs to the cold virus, so a second injection would be ineffective.

In this new trial, multiple injections are possible.  They don't use a virus.  Apparently they use a laser to poke a hole in the cells so that the ZFN's can get in there.  This seems like total science-fiction and it must be a tiny laser.  But the upshot is since no viral vector is used, you don't get ABs, and you can get multiple injections.

In this trial, people will be receiving up to 3 injections.  You get the injection, go on a STI, see what happens! 

George
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on June 24, 2014, 01:33:27 am
Best Luck!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on June 24, 2014, 12:09:19 pm
Yes, best of luck.  I'm hoping they enroll you.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on June 26, 2014, 12:19:08 pm
I went in yesterday to Quest to get screened for the Sangamo trial.   As I mentioned before, they are using a laser to blast the wholes in the cells to let the ZFN get in there and do the work of modifying the cell.  So the process is apherisis, modify the cells, put them back in.  Because there are not using a virus as a vector, this should work better as one's body won't be producing ABs to the viral vector.

They have to do a tropism test.  30% of those come back as "no result" b/c there is not enough virus in the blood to obtain a sample.  If I come back as CCR5 only, then I'll be eligible for the trial, which won't be until October/Nov.

Other news:  The monoclonal AB trial is going well.  Most getting UD as long as they are taking it (weekly injection).  Also, CalImmune second arm should be starting soon.  The conditioning is going to be necessary to get the modified stem cells into the marrow.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Jmarksto on June 26, 2014, 04:28:03 pm
Thanks for the update geobee, and wishing you the best on the test and trial - thank you.

Also, do the monoclonal AB's penetrate the reservoirs?

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on June 26, 2014, 08:10:25 pm
I don't know if the AB's penetrate the reservoirs or not.  I'm guessing that they don't.  From what I read before, the virus comes back after you stop the AB treatment.

What a person at Quest did say as that the participants in the study had a favorable view of the injections which allowed them to not take daily meds.  For me, I'd rather take meds than inject myself.



Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Jmarksto on June 26, 2014, 10:22:57 pm
Given that the ABs go directly to the blood stream I would expect fewer side effects (even minor ones).  I think I would prefer the injections - even if it was just to eliminate or adjust my lunch schedule a little more.  It would be nice to have the option anyway.

Thanks again for posting, interesting stuff!
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on July 23, 2014, 11:20:21 am
Another article from today's SFGate talking about the Sangamo and Calimmune stem cell trials and their potential to effect a functional cure.

http://www.sfgate.com/health/article/Stem-cell-therapy-could-lead-to-HIV-cure-5640362.php

Stem cell therapy could lead to HIV cure
Erin Allday
Published 5:02 am, Wednesday, July 23, 2014

Two teams of scientists with strong ties to the Bay Area are racing to develop a stem cell therapy that would provide a practical cure for people living with HIV infection, leaving them with an immune system capable of keeping them healthy without daily medication even as some virus remains circulating in their bloodstream.

Both groups of researchers are trying to capitalize on the DNA of so-called elite controllers - people who are naturally resistant to HIV due to a genetic mutation that prevents the virus from latching on to their immune cells. It was an elite controller who donated bone marrow to Timothy Brown, the "Berlin patient," who was the first in the world to be cured of HIV. Doctors attribute Brown's rebuilt HIV-resistant immune system to the genetic mutation in the bone marrow.

Bone marrow transplants are not an effective cure for HIV for the general population because they're risky and expensive. But stem cells, drawn from a patient's own bone marrow and altered to be HIV-resistant, may be able to do the job using the same premise.

"If you could make a person's immune system mutated in a way that HIV could not infect it, then you may be able to cure the HIV," said Dr. John Zaia, a virologist with the Beckman Research Institute near Los Angeles, who's working with Sangamo Biosciences in Richmond on a technique to engineer and transplant stem cells. "That's the premise anyway," he said. "And it's based on that one case in the Berlin, that one transplant."

The teams at the forefront of stem cell HIV therapy are led by Sangamo and Calimmune, a San Diego company that is testing its treatment in patients in Los Angeles and San Francisco.

Calimmune was the first to start human clinical trials, in July 2013, and last month reported that the first group of patients was doing well enough that they were ready to begin treating a second group. Sangamo expects to start clinical trials as early as this fall.

Both groups are being funded in part by the California Institute for Regenerative Medicine, the state's stem cell agency.

The research is based on the discovery in the mid-1990s of a specific genetic mutation that blocks a protein called CCR5. The protein is found on the surface of some cells where it acts as a receptor, allowing HIV to attach and ultimately fuse with the cell. Without CCR5, it's much more difficult, although not impossible, for the virus to infect a cell.

Genetic mutation

In elite controllers, the CCR5 receptor is mutated in such a way that HIV cannot latch onto it. Scientists believe that only about 1 percent of people worldwide have the CCR5 genetic mutation.

Nearly 10 years ago, when Timothy Brown needed a bone marrow transplant to treat his newly diagnosed leukemia, his doctor in Berlin decided to attempt an experiment, and chose a donor who was known to be an elite controller.

Bone marrow contains stem cells that stay active during a person's lifetime, constantly replenishing the cells that make up their blood and immune system. In a bone marrow transplant, stem cells from the donor replace the patient's own stem cells and build a new immune system.

Brown had been HIV-positive since about 1995, and his doctor wondered if replacing his immune system with cells from a donor who was naturally resistant would kill the virus and cure the leukemia at the same time. It worked.

But bone marrow transplants are risky procedures - patients can die from rejection of the donor cells or from infection while their immune system is rebuilt from scratch. They're also expensive and require lengthy recovery. And it's impractical to collect donor tissue only from the rare individuals who are elite controllers.

So bone marrow transplants aren't considered a worthwhile treatment for everyone who has HIV, especially since antiretroviral drugs are so effective.

Instead, scientists believe that they can draw stem cells from the bone marrow of patients infected with HIV, and genetically engineer those cells so that they have the mutated CCR5 receptor. Then, the same cells can be transplanted back into patients, where they will supply the immune system with cells that are HIV-resistant.

'Warrior cells'

"By actually treating the patient's own cells and giving them back, you're essentially helping to engineer an immune system that becomes long-term protective against HIV," said Dr. Louis Breton, chief executive of Calimmune. "The stem cells give the patient a group of highly protected warrior cells to do the job that we want our immune system to do, which is to kill off any disease and virus."

In theory, once the stem cells are implanted in the patients again, they'll be able to indefinitely replenish the immune system, and no further transplants or other treatments would be necessary.

Because scientists don't plan to destroy the patients' old immune system before transplanting the engineered stem cells, patients would continue to make cells that are vulnerable to HIV.

But the hope is that enough of the HIV-resistant cells will be produced that the body will be able to mount an immune response to fight the virus and keep it in check - providing what's called a "functional" cure, in which the virus remains but doesn't cause damage.

"Obviously eradication of all viral strains in the system would be extraordinary," Breton said. "This step we're taking is essentially a one-time treatment instead of lifetime."

The same premise could someday help scientists build a vaccine against HIV. But for now, the two teams of scientists are focused on a specific group of patients - those who aren't doing well on antiretroviral therapy and are at risk of their infection developing into AIDS.

The Sangamo and Calimmune teams have different strategies for engineering their stem cells and transplanting them back into patients. But the basic premise is the same, and the teams are nearly neck-and-neck in their research.

Calimmune was the first to put the stem cells into patients. Sangamo hasn't begun clinical trials with stem cells yet, but earlier this year it reported some success from a study involving transplanted T-cells - a type of immune cell that is destroyed by HIV. The T-cells were genetically engineered to resist HIV, using a technique that Sangamo will apply to stem cells in upcoming trials.

Scientists familiar with the research said they're encouraged both by the premise of the stem cell work and the results that have been produced so far. But even if both teams are successful, the treatment won't be practical on a global scale until it's made much simpler, said Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology in San Francisco.

Ideal therapy

Ideally, doctors would like to see a therapy in which patients are given a single injection that causes their stem cells to be re-engineered in the body, without having to be removed and treated in a lab. If the ongoing research proves successful in causing a functional cure, Greene said, the next step would be developing a procedure that's much more efficient.

"A lot of the stem cell work involves transplants. As proof of principle, that's great, but when it comes to treating tens of millions of people, it's just not going to work," Greene said. "We always have to have in mind a scalable solution. We must avoid therapies that are only useful to 100 rich people in the world."

San Francisco resident Michael Petrelis said he understands the need to remain wary of any promise of a cure - HIV is complicated, and there may never be a single treatment or therapy that works for everyone to wipe out the disease. But he said hope is something that helps keep him going.

"In addition to my AIDS cocktail, one of the things that's helped keep me alive is my hope for a cure," said Petrelis, 55, who has lived with HIV for more than a decade. "I'm optimistic that I can survive long enough to take advantage of stem cell research or something else.

"A lot of times, the researchers and even people with AIDS say we shouldn't use that 'C' word," he said. "And I'm of the thinking that yes, we should. We have to."
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on July 24, 2014, 02:25:54 am
One patient remains off therapy with control viral load for over a year
and another one for 34 weeks.

I think this approach will eventually work. It is just a matter how they can get enough resistant CD4 cells (20-30% is pretty good. the more the better of course).

Hope for the best.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dico on July 24, 2014, 04:40:44 pm
In previous studies, mathematical models have shown that we need at least 50% of our peripheral blood to be changed in order to have a long term remission.

They can change at best 20 to 30% of the PBMC so it won't lead to a cure.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on July 24, 2014, 06:19:16 pm
Quest let me know that I've passed the first round of qualifications for the trial.  One day I may find out for myself whether this works or not!  (Once I start the trial, I'm embargoed from telling the results until it's over).
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on July 24, 2014, 08:52:10 pm
In previous studies, mathematical models have shown that we need at least 50% of our peripheral blood to be changed in order to have a long term remission.

They can change at best 20 to 30% of the PBMC so it won't lead to a cure.

Which study shows that at least 50% is needed? If the study doesn't consider ccr5 mutation even 100% is useless like the Boston patients. Btw both two sangamo patients have experienced longer remission despite having only around 20% cells modified. my feeling is that modifying stem cell is the ultimate cure :)

Also. With the ability to retreat. Mathematically they can achieve over 50% modification with multiple treatments
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on July 24, 2014, 08:56:08 pm
Quest let me know that I've passed the first round of qualifications for the trial.  One day I may find out for myself whether this works or not!  (Once I start the trial, I'm embargoed from telling the results until it's over).

Glad to hear that!!! I pray that you will get benefits from it. Hopefully one day I can be in the trial too. Especially the stem cell one
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on September 05, 2014, 11:23:39 am
And then there's this from the New England Journal of Medicine:

http://www.nejm.org/doi/full/10.1056/NEJMc1405805

Shift of HIV Tropism in Stem-Cell Transplantation with CCR5 Delta32 Mutation

N Engl J Med 2014; 371:880-882August 28, 2014DOI: 10.1056/NEJMc1405805
 
Article

To the Editor:

Infection with the human immunodeficiency virus (HIV) requires entry into target cells by binding of the viral envelope to the CD4 receptor and to either the chemokine (C-C motif) receptor 5 (CCR5) or the chemokine (C-X-C motif) receptor 4 (CXCR4). Homozygosity for a 32-bp deletion in the CCR5 allele (CCR5 delta32) prevents cellular entry of CCR5-tropic (R5-tropic) HIV type 1 (HIV-1) strains. In 2009, there was a report1 about an HIV-1–infected patient with acute myeloid leukemia in whom the viral load remained undetectable after allogeneic stem-cell transplantation from a donor who was homozygous for the CCR5 delta32 mutation and after the discontinuation of antiretroviral therapy. This case gave rise to hope for new strategies for eradicating HIV-1 infection. However, this case has remained unique. Furthermore, in HIV-1–infected patients undergoing allogeneic stem-cell transplantation from donors with nonmutated CCR5, viral rebound has been reported.2

Here, we present the case of a 27-year-old patient with HIV-1 infection and anaplastic large-cell lymphoma. Because of a poor prognosis after progression of the T-cell lymphoma, stem-cell transplantation was planned, and a donor who was homozygous for the CCR5 delta32 mutation was identified. We determined the viral tropism of HIV-1 by genotyping the V3 amino acid sequence and applying geno2pheno bioinformatic software to predict viral coreceptor use,3 which indicates the probability of classifying an R5-tropic virus falsely as a CXCR4-tropic (X4-tropic) virus (false positive rate of <5%, X4-tropic; false positive rate of 5 to 10%, intermediate; false positive rate of >15%, R5-tropic). Before the patient underwent transplantation, the tropism from viral RNA was predicted to be either R5-tropic (false positive rate, 24.7%) or intermediate (false positive rate, 8.2%), whereas the V3 sequence from proviral DNA was classified as intermediate (false positive rate, 6.6%) or X4-tropic (false positive rate, 4.4%).

The patient discontinued antiretroviral therapy before the initiation of myeloablative treatment but resumed therapy 3 weeks after transplantation because of a rebound of 93,390 copies of HIV RNA per milliliter (Figure 1Figure 1 Human Immunodeficiency Virus (HIV) Levels, HIV Tropism, and Effect of Antiretroviral Therapy in a Patient with Anaplastic Large-Cell Lymphoma.
). The V3 sequence was related to the previous genotypes from this patient, as indicated by the presence of identical mutations in all V3 sequences (see the table in the Supplementary Appendix); it also carried several specific mutations resulting in the prediction of an X4-tropic virus (false positive rate, 0.4%). Antiretroviral therapy effectively suppressed viral replication until the patient had a relapse of the T-cell lymphoma, when antiretroviral therapy was again stopped. Two weeks before the patient died, the HIV-1 RNA level was 7,582,496 copies per milliliter.

The genotypic analyses of HIV-1 variants in this patient showed a shift from a dominantly R5-tropic HIV before stem-cell transplantation toward an X4-tropic HIV after transplantation. This shift of tropism was probably driven by transplantation with stem cells homozygous for the CCR5 delta32 mutation. This case highlights the fact that viral escape mechanisms might jeopardize CCR5-knockout strategies to control HIV infection.4

Lambros Kordelas, M.D., Ph.D.
Jens Verheyen, M.D.
Stefan Esser, M.D.
University of Duisburg–Essen, Essen, Germany
lambros.kordelas@uk-essen.de

for the Essen HIV AlloSCT Group
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: tryingtostay on September 05, 2014, 11:26:38 am
What does all that ^  mumbo jumbo say? 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 05, 2014, 12:02:36 pm
What does all that ^  mumbo jumbo say?

Guy had ccr5 tropic virus, he got a stem cell transplant with stem cells from a ccr5 delta 32 deleted donor (just like the Berlin patient did) then his virus rebounded with cxcr4 tropic virus, then the patient died. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ptrk3 on September 05, 2014, 12:15:23 pm
I think that the "mumbo jumbo" points out that HIV is a wily bastard that can adjust its specific genotype population to specifically-tailored genotype eradication attempts (one genotype is attacked so if the patient has multiple genotypes of HIV the genotype not eradicated will thrive and take over):  http://en.wikipedia.org/wiki/Host_tropism

At the very least, the letter points out that one type of treatment won't be a universal cure. 

I'm starting to understand that I'm going to be on Atripla for the rest of my life :'(

Is this the "take away" other people on the forum take from this letter?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 05, 2014, 12:19:28 pm


At the very least, the letter points out that one type of treatment won't be a universal cure. 

I'm starting to understand that I'm going to be on Atripla for the rest of my life :'(

Is this the "take away" other people on the forum take from this letter?

Dude you won't be on Atripla for the rest of your life.  My god Atripla is an older and nasty ass med.  But, your gonna be on treatment for the rest of your life.  Move to a new med with less side effects and get comfortable because it's going to be a long ride.

Oh, I didn't take that away from this report.  This report is interesting but it's one patient who sadly appeared to be very sick with advanced cancer and HIV and died.  Poor guy.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ptrk3 on September 05, 2014, 12:30:20 pm
Yeah, but I was hoping that I wouldn't need to be on any treatment for the rest of my life and was thinking that there might be a cure soon.

Thanks, though, for your realistic perspective.  You have adjusted and accepted your status well.  I wish I can do the same.

I frequently get seriously depressed because of my status.  Do you think it could be the Atripla (the sustiva) that contributes to my depression?  What other med should I seek?  I was diagnosed about 13 months ago and have been on Atripla ever since (my VL was undetectable in about 6 weeks).  I am still so sad and sometimes can't even leave the house.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Jeff G on September 05, 2014, 12:39:52 pm


I frequently get seriously depressed because of my status.  Do you think it could be the Atripla

If you are having bouts of depression that has gotten worse or began after Atripla then you probably need to make a change . I personally feel that if depression is a factor a person should never be put on this drug to begin with .
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ptrk3 on September 05, 2014, 12:45:22 pm
Thanks.  I see my ID the week after next.  I'll bring the matter up. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 05, 2014, 01:16:47 pm
Yeah, but I was hoping that I wouldn't need to be on any treatment for the rest of my life and was thinking that there might be a cure soon.



What's your definition of "soon"?  Everyone wants a cure for HIV and it will probably happen soon, if your definition of soon is measured in decades rather than months or years.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ptrk3 on September 05, 2014, 02:28:06 pm
Good question.  I was thinking of "soon" as within 10 years, but that does not seem likely after all, not at this point.  I'm in middle age, so decades could well be the rest of my life.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: tryingtostay on September 05, 2014, 02:57:51 pm
I was thinking of "soon" as within 10 years.

I believe 10 yrs or within is possible with the study at Temple. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ptrk3 on September 05, 2014, 04:01:18 pm
Thanks.  Within 10 years, that would be nice, indeed! :)
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: tryingtostay on September 05, 2014, 04:46:29 pm
Thanks.  Within 10 years, that would be nice, indeed! :)

I believe it is the best way to go above all else.  What better way to remove HIV-1 from the body than to remove it from the DNA?  The problem is the delivery method last I gathered.  I believe this is the best hope above all other research.  I know there was a geneticist in here doubting the study with his knowledge and research with HIV-1 but he pointed out that it's only because gene therapy is in it's infancy.  It's coming and what I think is other cures will come along with it!  And that's fucking fantastic for all mankind
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: hotguyinTX on September 05, 2014, 09:27:42 pm
Interesting. Actually there is one recent study showing that people with Delta32 mutation is losing their "resistance" to HIV because so many HIV+ people have cxcr4 strains while people with two genes called rs9264942 still maintain viral control which is likely due to the way their immune system handle the infection rather than the mutation that prevent HIV infection or slows replication. 

http://www.pubfacts.com/detail/21860345/Rising-HIV-1-viral-load-set-point-at-a-population-level-coincides-with-a-fading-impact-of-host-genet

But on the other hand, it clearly shows that HIV virus do need some receptors to replicate - what happens if we engineer cells to lack cxcr4 and delta32? Or are there other "doors" for them to open?
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 06, 2014, 01:20:18 am
I'm still in the running for the Sangamo trial.  As I mentioned above, one of the things they have to do a tropism test to see if you have CCR5 virus.   Since they have so little virus to test (if you're UD), they often can't determine this.    Also, it takes months (apparently) to complete.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 06, 2014, 12:39:41 pm
I'm still in the running for the Sangamo trial.  As I mentioned above, one of the things they have to do a tropism test to see if you have CCR5 virus.   Since they have so little virus to test (if you're UD), they often can't determine this.    Also, it takes months (apparently) to complete.

Ya but the Sangamo trial isn't a clinical trial to cure HIV at this point anyway.  It's pretty much already been determined not to cure HIV (treating only cd4 cells) but may improve cd4 recovery and may possibly offer a clinical improvement. Possibly, maybe.

Sangamo and City of Hope are now looking to see if treating and transplanting hematopoietic stem cells could cure the infection http://defeathiv.org/institutions/
And
http://defeathiv.org/clinical-studies/

But they are ONLY doing clinical trials on patients with cancer who are getting a stem cell transplant anyway.


Even so....this research is still decades from actual clinical significance.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on September 06, 2014, 01:39:55 pm

But they are ONLY doing clinical trials on patients with cancer who are getting a stem cell transplant anyway.


Your other comments can be insightful, but that is just blatantly incorrect when it comes to Sangamo's upcoming HSC trial.  Assume you're only referring to the COH trial.

Quote
Even so....this research is still decades from actual clinical significance.

Really?  Better let CIRM know they're wasting millions of dollars of taxpayer money on a hoax.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 06, 2014, 02:17:50 pm
Show me where I said it was a hoax?  I just saw a presentation from Paula Canon who pretty much said the said the same thing
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on September 06, 2014, 02:44:27 pm
Paula Cannon said we were "decades away" from modified HSC efficacy in the clinic?  Given the certainty with which you proclaim your hyperbolic assertions I'm surprised you didn't post a link.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 06, 2014, 04:48:16 pm
I think you misunderstood the point.

The current Sangamo and Calimune trials that are treating cd4 cells and infusing them back into the patient are not expected to yield results that will in effect cure the patient.   They may offer a clinical benefit by 1. Restoring cd4 counts in patients who's cd4's don't recover after HAART and restoring cd4/8 ratio to normal.

However, the FDA will only approve this as a treatment IF this a. turns out to be true and b. actually shows that this affects outcomes meaning does raising a cd4 count and restoring the cd4/8 ratio have clinical meaning?   The only way to determine that is with a phase 3 trial that measure outcomes.  Meaning...a very long clinical trial and we aren't anywhere near starting that (so at least a decade here). 

2.  Can the current treatment lower the viral load to say <200 without HAART?  Not expecting a cure but maintaining a low viral load without treatment?  The obstacles to this are enormous and currently not expected.  Even so, let's say it does maintain a low level viral load.  If it's not low enough the virus will mutate and your whole concept is shit.  The only way the FDA will approve such a treatment when there are currently effective and well tolerated treatment is if it can show clinical benefit over a long period of time.  Again, we are no where near a phase 3 trial and the duration of that trial would need to be significant.   Especially when just last week it was shown that over time it's quite possible your modified immune system that's resistant to ccr5 tropic virus won't matter since it's mutating to become cxcr4 tropic. 

3.  There is the idea that completely destroying ones immune system with chemotherapy and radiation and rebuilding it from scratch using modified stem cells using sangamo's system could lead to eradication (cure).   The NIH has funded this idea with >$20 million grant.  Sangamo and City of Hope and Fred Hutch (who invented the stem cell transplant) are studying this.  Clinical trials at this point are ONLY open to hiv positive patients with cancer.  I posted the links above.  Just last week there was a conference about this work with many speakers including Francois Barre-Synoise, Paula Cannon, Hans Peter Kiem, Keith Jerome among others.  I can tell you NOT ONE OF THEM is expecting a "cure" any time soon.  Especially using this technology.  It's too soon  and currently too dangerous. 

Read the links I posted above. 

PS. Everyone is free to hope.  If you want to believe this will cure you, knock yourself out. 

Personally I'd rather take a Stribild or Tivicay/Truvada then be irritated and exposed to high dose chemo and a stem cell transplant.....no thank you.

>>>Does anyone really think the FDA is going to approve any of this when we currently have effective and well tolerated treatments that basically restore life expectancy to near normal?  This needs to hit a fucking grand slam to get approved and so far, I don't see it.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Ptrk3 on September 06, 2014, 05:05:54 pm
Thanks, to all the folks in this thread for their spirited and intelligent discussion of this topic.  I'm learning much from reading the links and back-and-forth.  I appreciate the time folks are spending in expressing complicated thoughts in easy-to-understand language for the rest of us.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 06, 2014, 05:30:10 pm
Thanks, to all the folks in this thread for their spirited and intelligent discussion of this topic.  I'm learning much from reading the links and back-and-forth.  I appreciate the time folks are spending in expressing complicated thoughts in easy-to-understand language for the rest of us.

Don't forget none of us are scientist so everything we say (me included) is really..well..shit.  So feel free to jump in
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on September 07, 2014, 12:47:09 am
I think I should point out that the Calimmune trial is not only treating CD4 cells but also Hematopoietic Stem/Progenitor Cells. Because Cal-1 is DNA based and treats HSPC's, which will divide and differentiate into immune system cells, more and more HIV resistant cells will be produced over time.

I should also point out that Cal-1 includes a fusion inhibitor which is there to attempt to block any non-CCR5 cell entries.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on September 07, 2014, 03:25:15 am
I agree that the Sangamo trial isn't a cure attempt, probably.  But... and it's a big but... it's better than the earlier trials.  In the old trial, you could only get one infusion b/c your body would create an antibody to the delivery vector.  In the new trial, you can get more than one infusion b/c the cells are being modified differently.   I don't think this will make a difference, but it might.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dico on September 07, 2014, 04:10:58 am
I agree that the Sangamo trial isn't a cure attempt, probably.  But... and it's a big but... it's better than the earlier trials.  In the old trial, you could only get one infusion b/c your body would create an antibody to the delivery vector.  In the new trial, you can get more than one infusion b/c the cells are being modified differently.   I don't think this will make a difference, but it might.

It will make a difference but the problem is that HIV can mutate. So the CCR5 knockdown will only temporarily work. There are no preclinical studies showing monkeys or rabbits have been cured using gene therapy.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: JakaTingkir on September 07, 2014, 10:08:26 am
It will make a difference but the problem is that HIV can mutate. So the CCR5 knockdown will only temporarily work. There are no preclinical studies showing monkeys or rabbits have been cured using gene therapy.
g
why do you need rabbits n monkeys?...there is human got cure about this method aka berlin patient...

the key point is how to make the body produce NEW modified cd4 cells. That’s my thought.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: bmancanfly on September 07, 2014, 03:44:50 pm
Anyone who wants to understand how slow research progresses,  just look at how long this thread has been going on.

And this treatment is nowhere close to being ready for prime time.  Let alone a "cure".
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: buginme2 on September 07, 2014, 03:50:27 pm
Anyone who wants to understand how slow research progresses,  just look at how long this thread has been going on.

And this treatment is nowhere close to being ready for prime time.  Let alone a "cure".

Hahaha for real this thread started six years ago and sure they have moved forward a little bit but. ....

Not to mention when/if this doesn't work... me thinks there's going to be a lot of pissed off poz forum members. 


I don't think I've seen such investment in one particular area of research.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: tryingtostay on September 10, 2014, 12:19:09 am
So the big hurdle with alot of these trials is to sustain the immune cells?  Then what?  I'm no expert but there will be problems with HIV still in the blood when and after they find a way to make our immune cells well, immune to HIV. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Matts on September 25, 2014, 06:13:08 pm
A case study from á german university:

a patient got a stem-cell transplantation with CCR5-Delta 32 mutation. The receptor switched from CCR5 to CXCR4 and the Patient died at the end with a viral load of > 7 Million copies. Maybe it is illusive to believe in  a cure with a CCr5 knockout-strategy.

Timothy R. Brown just had luck and is  a special single case. Correct me if I am wrong.

http://www.nejm.org/doi/full/10.1056/NEJMc1405805 (http://www.nejm.org/doi/full/10.1056/NEJMc1405805)

http://cid.oxfordjournals.org/content/59/4/596.long (http://cid.oxfordjournals.org/content/59/4/596.long)

"Shift of HIV Tropism in Stem-Cell Transplantation with CCR5 Delta32 Mutation

Infection with the human immunodeficiency virus (HIV) requires entry into target cells by binding of the viral envelope to the CD4 receptor and to either the chemokine (C-C motif) receptor 5 (CCR5) or the chemokine (C-X-C motif) receptor 4 (CXCR4). Homozygosity for a 32-bp deletion in the CCR5 allele (CCR5 delta32) prevents cellular entry of CCR5-tropic (R5-tropic) HIV type 1 (HIV-1) strains. In 2009, there was a report1 about an HIV-1–infected patient with acute myeloid leukemia in whom the viral load remained undetectable after allogeneic stem-cell transplantation from a donor who was homozygous for the CCR5 delta32 mutation and after the discontinuation of antiretroviral therapy. This case gave rise to hope for new strategies for eradicating HIV-1 infection. However, this case has remained unique. Furthermore, in HIV-1–infected patients undergoing allogeneic stem-cell transplantation from donors with nonmutated CCR5, viral rebound has been reported.2

Here, we present the case of a 27-year-old patient with HIV-1 infection and anaplastic large-cell lymphoma. Because of a poor prognosis after progression of the T-cell lymphoma, stem-cell transplantation was planned, and a donor who was homozygous for the CCR5 delta32 mutation was identified. We determined the viral tropism of HIV-1 by genotyping the V3 amino acid sequence and applying geno2pheno bioinformatic software to predict viral coreceptor use,3 which indicates the probability of classifying an R5-tropic virus falsely as a CXCR4-tropic (X4-tropic) virus (false positive rate of <5%, X4-tropic; false positive rate of 5 to 10%, intermediate; false positive rate of >15%, R5-tropic). Before the patient underwent transplantation, the tropism from viral RNA was predicted to be either R5-tropic (false positive rate, 24.7%) or intermediate (false positive rate, 8.2%), whereas the V3 sequence from proviral DNA was classified as intermediate (false positive rate, 6.6%) or X4-tropic (false positive rate, 4.4%).

The patient discontinued antiretroviral therapy before the initiation of myeloablative treatment but resumed therapy 3 weeks after transplantation because of a rebound of 93,390 copies of HIV RNA per milliliter (Figure 1Figure 1Human Immunodeficiency Virus (HIV) Levels, HIV Tropism, and Effect of Antiretroviral Therapy in a Patient with Anaplastic Large-Cell Lymphoma.). The V3 sequence was related to the previous genotypes from this patient, as indicated by the presence of identical mutations in all V3 sequences (see the table in the Supplementary Appendix); it also carried several specific mutations resulting in the prediction of an X4-tropic virus (false positive rate, 0.4%). Antiretroviral therapy effectively suppressed viral replication until the patient had a relapse of the T-cell lymphoma, when antiretroviral therapy was again stopped. Two weeks before the patient died, the HIV-1 RNA level was 7,582,496 copies per milliliter.

The genotypic analyses of HIV-1 variants in this patient showed a shift from a dominantly R5-tropic HIV before stem-cell transplantation toward an X4-tropic HIV after transplantation. This shift of tropism was probably driven by transplantation with stem cells homozygous for the CCR5 delta32 mutation. This case highlights the fact that viral escape mechanisms might jeopardize CCR5-knockout strategies to control HIV infection.4 "




Lambros Kordelas, M.D., Ph.D.
Jens Verheyen, M.D.
Stefan Esser, M.D.
University of Duisburg–Essen, Essen, Germany
lambros.kordelas@uk-essen.de
---------------------------

About the Berlin Patient:

"Dependence on the CCR5 Coreceptor for Viral Replication Explains the Lack of Rebound of CXCR4-Predicted HIV Variants in the Berlin Patient

Abstract

The “Berlin patient” is the first patient cured of HIV-1 infection after allogeneic transplantation with nonfunctional CCR5 coreceptor stem cells. We demonstrate that CXCR4-predicted minority viruses present prior to transplantation were unable to rebound after transplantation due to their dependence on CCR5 for replication and high genetic barrier toward CXCR4 usage.

The “Berlin patient” is the first individual in whom human immunodeficiency virus (HIV) type 1 (HIV-1) infection has been cured following allogeneic transplantation to treat acute myeloid leukemia [1, 2]. The stem cells used were homozygous for the Δ32 frameshift mutation (CCR5Δ32), resulting in absence of the CCR5 receptor at the cellular surface [3]. Heterozygosis for CCR5Δ32 is associated with slower disease progression, and individuals homozygous for CCR5Δ32 are naturally resistant to CCR5-tropic HIV [3]. Binding of the viral envelope glycoprotein gp120 to a coreceptor (CCR5 or CXCR4) is essential for HIV entry into CD4+ host cells. HIV coreceptor tropism is mainly determined by the third hypervariable loop of the viral envelope (gp120-V3) [4].

The Berlin patient had a plasma viral load of 6.9 × 106 copies/mL during an episode of treatment interruption prior to stem cell transplantation (SCT). The viral population was predicted to be CCR5-tropic based on standard genotypic tropism testing (Geno2Pheno[coreceptor] false-positive rate [FPR] 24.2%) [1]. Detailed analysis using ultradeep sequencing detected a 2.9% minority viral population predicted to be CXCR4-tropic (Geno2Pheno[coreceptor] FPR range, 2.7%–9.3%). Two months after SCT, successful reconstitution of CD4+ T cells with the homozygous CCR5Δ32 phenotype was observed [1]. These donor derived T cells displayed normal levels of CXCR4 coreceptor surface expression. Given the detection of CXCR4-predicted viral variants prior to SCT, one would expect these variants to appear after SCT, especially as antiretroviral therapy was discontinued during the transplant procedure. However, no viral rebound was observed, and the patient remained free of HIV infection for >5 years post-SCT [5].

Previously, we demonstrated that some viruses capable of using CXCR4 have a clear CCR5 coreceptor preference in vivo [6]. Based on these findings, we postulate that a rebound of the CXCR4-predicted variants in the Berlin patient did not occur due to dependence on the CCR5 coreceptor for viral replication.
...................

DISCUSSION

The Berlin patient is the first patient with a cured HIV infection. Prior to SCT, the viral population was genotyped and a minority population was predicted to use the alternative CXCR4 coreceptor in a Web-based algorithm (Geno2Pheno[coreceptor]) [1]. Considering the normal levels of CXCR4 coreceptor expression on the donor-derived cells and susceptibility of these cells for CXCR4-tropic virus, it was remarkable that HIV did not rebound post-SCT in the absence of combination antiretroviral therapy (cART) [2]. Our study demonstrates that CXCR4-predicted minority viruses present prior to transplant were unable to rebound after transplant due to their dependence on CCR5 for replication and a high genetic barrier toward CXCR4 usage.

The main determinant of coreceptor usage is the gp120-V3 loop. Genotypic prediction algorithms, such as Geno2Pheno[coreceptor], use this region to predict coreceptor tropism. The result of the Geno2Pheno[coreceptor] interpretation is given as a quantitative value, the FPR, which defines the probability of classifying a CCR5-predicted virus falsely as CXCR4-predicted variant. Varying the threshold value for FPR classification changes the sensitivity and specificity for CXCR4 tropism prediction. In clinical practice, conservative cutoff FPR values that show good correlations with virological outcome during CCR5 inhibitor–based therapy are generally applied to prevent underestimation of the presence of CXCR4-tropic viruses (FPR cutoffs 3.5%–10%) [11, 15]. The lowest FPR of the minority variants in the Berlin patient prior to SCT was 2.7%. Although this is below the lowest cutoff FPR suggested for tropism prediction based on deep sequencing (3.5%) and therefore genotypically predicted to be CXCR4-tropic, the variant was dependent on CCR5 for viral entry in phenotypic assays. This single case study shows that predicted genotypic coreceptor tropism may not always reflect biological behavior and suggests that larger studies are needed to explore the use a lower cutoff FPR for maraviroc eligibility in clinical practice. In case of a CCR5Δ32-SCT procedure, a more lenient FPR and/or phenotypic testing should be considered.

Envelope regions outside the gp120-V3 sequence can modulate coreceptor affinity [16], and commercial phenotypic coreceptor usage assays are based on (near) full-length envelope sequences representing the plasma population virus [11]. Unfortunately, prior to SCT, full envelope sequences were not generated from the Berlin patient, and no additional samples were stored to enable full envelope sequencing. Therefore, we were inherently limited in assessment of the coreceptor phenotype of the minority variants and were restricted to the V3 loop sequences generated by ultradeep sequencing prior to SCT. In absence of patient-derived full envelope sequences, we decided to clone the gp120-V3 loop sequences of the Berlin patient in the background of a CXCR4-tropic HIV-1 laboratory strain to limit bias for CCR5 usage.

In the Berlin patient, CCR5-tropic permissive cells could still be detected for at least 5.5 months in the colon, and proviral DNA was observed 2 months after SCT [1, 2]. More than 5 years post-SCT, extremely low levels of HIV DNA and RNA were intermittently detected using very sensitive assays [5]. Given the volatile combination of long-lived CCR5-expressing cells and a potential CCR5-tropic reservoir, HIV replication could potentially have continued. Residual replication of CCR5-tropic viruses in the setting of increasing numbers of CCR5−CXCR4+ cells may then result in evolution toward CXCR4 usage. We tested the evolution potential for the most CXCR4-predicted patient-derived viruses and did not observe viral evolution toward CXCR4 usage, suggesting a relatively high barrier for coreceptor switch. Moreover, it has also been hypothesized that the number of residual CCR5-expressing CD4+ cells after SCT was too low to support replication of the CCR5-tropic variants and therefore evolution toward CXCR4 usage [17].

A recent study in which 2 HIV-infected heterozygote CCR5Δ32 patients with a small viral reservoir received a CCR5WT/WT transplant in the presence of cART unfortunately demonstrated viral rebound after interruption of cART [18, 19]. In the Berlin patient, aside from absence of CXCR4-tropic virus, the lack of a rebound of CCR5-tropic virus immediately post-SCT in the absence of cART indicates that transplantation of CCR5Δ32/Δ32 stem cells was pivotal to the apparent cure of HIV. These results provide a rationale for CCR5-based SCT and gene therapy studies in which in-depth analysis of HIV coreceptor usage is essential.
.....
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: greenbean on September 26, 2014, 03:12:47 am
I still believe gene therapy is a promising approach to cure HIV. Again, the problem is delivery and it won't be a cure for everyone. (e.g. people with dual tropism)

Page 14 of this presentation shows a hetero controlling viral load for over a year

http://files.shareholder.com/downloads/SGMO/3465274679x0x780854/8f05992e-1a46-41b2-904d-040803103d0a/MS%20NYC%20091014%20FINAL.pdf

Page 15 showing two patients without CCR5 mutation controlling viral load without HART.

looks like it is heading to the right direction
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on September 26, 2014, 07:55:08 am
Timothy R. Brown just had luck and is  a special single case. Correct me if I am wrong.

Or maybe this guy just had bad luck and is a special single case?  We have no way of knowing of course, but unprovable doom and gloom assertions delivered as fact provide nothing.

Btw, Tim Brown was reported to be dual tropic pre-stem cell transplant.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: leatherman on September 26, 2014, 04:46:14 pm
Timothy R. Brown just had luck and is  a special single case. Correct me if I am wrong.
interesting links you provided - but they said nothing about what the man himself went through. While all that biological/scientific stuff is certainly intriguing, Tim Brown himself went through HIV, acute myeloid leukemia, chemotherapy, antiretrovirals, radiation, Stem cell transplant, relapse of acute myeloid leukemia, a second Stem cell transplant, leukoencephalopathy, colonoscopies, liver biopsies, major side effects, physical therapy, extended recovery time.... while the man is lucky to be alive because just one of any of those issues had a huge potential of causing his death, if I was him I don't know that I would be feeling all that "lucky".

http://onlinedigeditions.com/display_article.php?id=1280628
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dico on October 27, 2014, 04:48:49 am
Hi Geobee,

Before you are being embargoed tell us what are the news about the Sangamo trial ? What dose of cyclo you will take (1 mg or 1,5 mg ?)

Thanks
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: geobee on October 27, 2014, 12:45:32 pm
Hi dico --

I'm not on the trial yet.  They said it might take a while.  They have to do a tropism study to see if I'm CCR5 or X4.  Because I'm undetectable it takes a long time for them to get enough sample to do it.   They said it would be a few months -- and it has.  I'll give them a call and see what's up.

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: dico on October 27, 2014, 02:03:19 pm
Thank u for ur swift reply.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on October 28, 2014, 08:52:41 pm
Looks like Sangamo was granted a US patent today, 10/28/14, to modify / knock out CXCR4 for "treatment and prevention of CXCR4-tropic HIV infection" using their Zinc Finger tech.  Normally I'd paste the body of the article to this post, but it's so long I'm just going to give a link.

http://www.investorvillage.com/smbd.asp?mb=1933&mn=68693&pt=msg&mid=14313758

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Hoyland on November 04, 2014, 09:31:42 pm
http://www.youtube.com/watch?v=plvv07vd5iI

A talk by Paula Cannon about HIV cure with gene therapy.
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on November 05, 2014, 08:36:57 pm
It's good to see that Paula Cannon is hoping to get approval to start a clinical trial with USC/City of Hope/Sangamo using hematopoietic stem cells in January, 2015. 
Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: freewillie99 on January 29, 2015, 01:25:02 pm
And here....we....go...

Giving HIV the [zinc] finger: using targeted nucleases to create an HIV-resistant Immune system.

Dr. Paula Cannon's presentation 1/27/15

http://mediacast.ic.utoronto.ca/20150127-OSCI/index.htm#

Sounds like the long awaited HSC trial will begin "any day now". 

Title: Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
Post by: Cosmicdancer on February 26, 2015, 10:19:34 am
Sangamo BioSciences Presents New Clinical Data at CROI 2015 From Trial of ZFP Therapeutic® Designed to Provide Functional Control of HIV

Data Demonstrate Cytoxan Preconditioning Combined with CD4/CD8 ZFN-modified T-cell Product Reduces Viral Load to Limit of Quantification in One Subject of Three; Delays Onset of Viremia in Another Subject

Company Also Announces FDA Acceptance of IND Application for New HIV/AIDS Clinical Trial Using ZFN-modification of Hematopoietic Stem Cells
RICHMOND, Calif., Feb. 26, 2015 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced the presentation of new clinical data from its Phase 1/2 clinical trial (SB-728-1101). The study is designed to evaluate SB-728-T, a ZFP Therapeutic® generated by ZFN-mediated genome editing of T-cells to knockout the CCR5 gene, which encodes a critical co-receptor for HIV infection. SB-728-T is being developed as a potential 'functional cure' for HIV/AIDS. The data were presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2015) which is being held in Seattle from February 23 to 26, 2015.

"In our studies of SB-728-T, we have observed remarkable effects on both the viral load and the levels of the viral reservoir," said Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "Data and models developed by other groups have defined the characteristics of so-called 'elite controllers' whose immune systems prevent their HIV infections from progressing to AIDS, without antiretroviral drugs (ART). As part of the 1101 study, we are evaluating whether an improvement in HIV control can be obtained by including CD8 T-cells in our SB-728-T product, mimicking a phenotype observed in 'elite controllers.'  The data demonstrate that we can generate a CD4/CD8 SB-728-T cell product that can be successfully combined with Cytoxan preconditioning to drive robust engraftment. Moreover, in the three subjects treated we have already observed encouraging increases in total CD8 T-cells and effects on the viral load during a treatment interruption (TI)."

The 1101 study was designed to evaluate the effect of increasing doses of Cytoxan® preconditioning as a method to maximize engraftment of ZFN- modified cells (SB-728-T) in which both copies of the CCR5 gene had been disrupted, making the cells fully resistant to HIV infection.  Data from Cohorts 1-5 of the 1101 study (18 subjects) demonstrated a dose-related increase in both total CD4 T-cell and ZFN modified CD4 T-cell engraftment in response to Cytoxan preconditioning up to 1.0 g/m2. In addition, all subjects underwent a TI and were taken off ART at sixteen weeks post infusion. Four subjects from Cohort 1-5 remain on long-term TI and have remained off ART for at least 40 weeks.

You can read the full press release here.

http://investor.sangamo.com/releasedetail.cfm?ReleaseID=898529