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Author Topic: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach  (Read 142966 times)

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Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #50 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/


Offline veritas

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #51 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

Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #52 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.
« Last Edit: December 16, 2010, 04:23:38 PM by Inchlingblue »

Offline wtfimpoz

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #53 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.
09/01/2009-neg
mid april, 2010, "flu like illness".
06/01/2010-weakly reactive ELISA, indeterminant WB
06/06/2010-reactive ELISA, confirmed positive.

DATE       CD4     %     VL
07/15/10  423     33    88k
08/28/10  489     19    189k
09/06/10-Started ATRIPLA
09/15/10  420     38    1400
11/21/10  517     25    51

Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #54 on: December 18, 2010, 01:25:38 PM »
wtf, I basically agree with what you say above.

Offline veritas

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #55 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!






Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #56 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?
« Last Edit: December 19, 2010, 08:17:04 PM by geobee »

Offline wtfimpoz

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #57 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. 
09/01/2009-neg
mid april, 2010, "flu like illness".
06/01/2010-weakly reactive ELISA, indeterminant WB
06/06/2010-reactive ELISA, confirmed positive.

DATE       CD4     %     VL
07/15/10  423     33    88k
08/28/10  489     19    189k
09/06/10-Started ATRIPLA
09/15/10  420     38    1400
11/21/10  517     25    51

Offline lmdo

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #58 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?


Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #59 on: December 22, 2010, 10:17:41 AM »
The last few posts have degenerated into ridiculous and speculative gobbly gook.  Give it a rest.
Beware Romanians bearing strange gifts

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #60 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."


Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #61 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.
Beware Romanians bearing strange gifts

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #62 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-naÔve, 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-naÔve 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."

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #63 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."



Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #64 on: February 10, 2011, 07:24:57 PM »
Thanks for the updates. ;)

Offline Cosmicdancer

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #65 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/
Summer, 2007 - &$#@?
November, 2007 - Tested poz, 300,000 vl, 560 cd4
Feb, 2008 - 57,000 vl, 520 cd4, started Atripla
June, 2008 - undetectable, 612 cd4
January, 2009 - undetectable, 670 cd4
May, 2009 - undetectable, 593 cd4
Sept, 2009 - 83 vl, 763 cd4, 34%
Dec, 2009 - undetectable, 889 cd4, 32%
April, 2010 - undetectable, 860 cd4, 31%
October, 2010 - undetectable, 800 cd4, 38%
April, 2011 - undetectable, t-cell test not done
October, 2011 - undetectable
April, 2012 - undetectable, 850 cd4, 39%
November, 2012 - undetectable, 901 cd4, 41%
April, 2013 - undetectable, 846 cd4, 36%
October, 2013 - undetectable
May, 2014 - undetectable, 784 cd4, 48%

Offline georgep77

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #66 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
Come on Sangamo,  Geovax,  Bionor immuno, ...Make us happy !!!
+ 2008

Offline Gio

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #67 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

Offline surf18

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #68 on: February 18, 2011, 11:36:46 PM »
sounds great. lets fast track this!

Offline sensual1973

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #69 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".
God grant me the serenity to accept the things i can not change.

Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #70 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.


Offline Hellraiser

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #71 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.

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #72 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. 


Offline Hellraiser

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #73 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.

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #74 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



Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #75 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

Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #76 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

Offline zadex

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #77 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).

Offline georgep77

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #78 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

                                     :(
Come on Sangamo,  Geovax,  Bionor immuno, ...Make us happy !!!
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Offline sensual1973

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #79 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.
God grant me the serenity to accept the things i can not change.

Offline zadex

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #80 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."

Offline Gio

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #81 on: February 28, 2011, 03:01:40 PM »
I just read the news myself.  I definitely wouldnt mind being part of the larger study... 

Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #82 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 arenít 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
« Last Edit: February 28, 2011, 08:34:40 PM by Inchlingblue »

Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #83 on: February 28, 2011, 08:36:19 PM »
I'm hoping and praying!!!!!

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #84 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.

BobF

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #85 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........

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #86 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?
Beware Romanians bearing strange gifts

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #87 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!


Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #88 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...

Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #89 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.

Offline Tim Horn

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #90 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/

Tim

Offline Tim Horn

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #91 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.
« Last Edit: March 02, 2011, 09:44:51 PM by Tim Horn »

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #92 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. 


BobF

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #93 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.

Offline bmancanfly

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #94 on: March 03, 2011, 02:52:06 PM »
 :-X
"The trouble with the world is that the stupid are cocksure and the intelligent are full of doubt."

 Bertrand Russell

Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #95 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."

BobF

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #96 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."

Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #97 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.

Offline Tim Horn

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #98 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.
« Last Edit: March 05, 2011, 08:30:30 AM by Tim Horn »

Offline Gio

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #99 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

 


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