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Author Topic: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach  (Read 144596 times)

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Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #100 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?

Offline Tim Horn

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #101 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.   

Offline coolstone25

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #102 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. ;)

Offline zadex

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #103 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


Offline Gio

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #104 on: March 07, 2011, 09:13:49 AM »
Tim thank you for the clarification

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #105 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/



Offline ppp333

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #106 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. 

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #107 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. 


Offline ppp333

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #108 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?

Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #109 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?

Offline simpleguy

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #110 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 ... :-\
2008 JUL: Sustiva OCT: Rayataz DEC: Kaletra • 2009 Off meds • 2011 Intelence • 2012+ Complera

Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #111 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.

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #112 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

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #113 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. 

Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #114 on: May 10, 2011, 07:43:52 PM »
Thanks for the update ;)

Offline newt

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #115 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
"The object is to be a well patient, not a good patient"

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #116 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

Offline Gio

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #117 on: July 11, 2011, 12:13:42 PM »
Here's hoping that more funds will be forth coming..   :) 

Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #118 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

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #119 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!
« Last Edit: July 28, 2011, 05:35:03 PM by geobee »

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #120 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.
Beware Romanians bearing strange gifts

Offline Mycen

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #121 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
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  :)

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #122 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
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.
Beware Romanians bearing strange gifts

Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #123 on: August 03, 2011, 08:01:59 PM »
Paula Cannon, gotta love her. Thanks for the links.

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #124 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.


Offline Inchlingblue

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #125 on: August 09, 2011, 08:21:13 PM »
It's definitely useful information which should help come up with a more precise methodology.

Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #126 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.  ;)

Offline Gio

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #127 on: August 17, 2011, 05:02:31 PM »
AWESOME AWESOME :)  Fingers crossed  ::)

Offline buginme2

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #128 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.

Offline Mycen

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #129 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.

Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #130 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.

Offline Coolio_7

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #131 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.

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #132 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!
« Last Edit: August 18, 2011, 09:12:01 PM by geobee »

Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #133 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?

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #134 on: August 20, 2011, 01:55:08 PM »

Offline buginme2

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #135 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/

Offline Hellraiser

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #136 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.

Offline Gio

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #137 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.. 

Offline mbpoz6

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #138 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)


Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #139 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

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #140 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.
 

Offline buginme2

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #141 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

Offline Gio

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #142 on: September 08, 2011, 08:09:35 PM »
Awesome....  Definitely on my calendar to look out for

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #143 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

Offline LM

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #144 on: September 12, 2011, 11:44:57 AM »
geobee, that's excellent, keep those news coming.

Offline sfpvguy41

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #145 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.
Labs: (undetectable since 2005)
12/13: 634 cdr, 37.3%, 758 cd8, total chol 183, triglycerides 131
8/13: changed to Edurant from Reyataz
12/12: 828 cd4, 34.5%, 1078 cd8, total chol 192, tri 196
12/11: 787 cd4, 37%, 979 cd8.
9/11: 758 cd4, 38%, 944 cd8, und.
8/11 dropped norvir, incr reyataz to 400 mg
6/11: 621 CD4 CD4% 41, CD8 680! Undetectable. Creatinine and eGFR are ok now.
Switched from Truvada to Epzicom in late April 2011
AGT/AST and creatinine back to normal mid-April.
Cut Norvir from regimen.
Switched back to Reyataz/Norvir late Feb 2011
2/11: CD4 664 34%, CD8 963, diagnosed with osteoporosis, high AGT/AST and creatinine.
12/10: CD4: 676 CD4%: 34 CD8: 1012
Switched from Reyataz/norvir to Isentress 10/10
8/10: CD4: 731 CD4%: 40 CD8: 866
Diagnosed Sept. 2002 started meds May 2005.

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #146 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.

Offline phildinftlaudy

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #147 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.
September 13, 2008 - diagnosed +
Labs:
Date    CD4    %   VL     Date  CD4  %   VL
10/08  636    35  510   9/09 473  38 2900  12/4/09 Atripla
12/09  540    30    60   
12/10  740    41  <48   
8/11    667    36  <20  
03/12  1,041  42  <20
05/12  1,241  47  <20
08/12   780    37  <20
11/12   549    35  <20
02/12  1,102  42  <20
11/12   549    35  <20


Offline sfpvguy41

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Abstract of Sangamo presentation today at ICAAC:immune system reconstitution
« Reply #149 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

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. 
Labs: (undetectable since 2005)
12/13: 634 cdr, 37.3%, 758 cd8, total chol 183, triglycerides 131
8/13: changed to Edurant from Reyataz
12/12: 828 cd4, 34.5%, 1078 cd8, total chol 192, tri 196
12/11: 787 cd4, 37%, 979 cd8.
9/11: 758 cd4, 38%, 944 cd8, und.
8/11 dropped norvir, incr reyataz to 400 mg
6/11: 621 CD4 CD4% 41, CD8 680! Undetectable. Creatinine and eGFR are ok now.
Switched from Truvada to Epzicom in late April 2011
AGT/AST and creatinine back to normal mid-April.
Cut Norvir from regimen.
Switched back to Reyataz/Norvir late Feb 2011
2/11: CD4 664 34%, CD8 963, diagnosed with osteoporosis, high AGT/AST and creatinine.
12/10: CD4: 676 CD4%: 34 CD8: 1012
Switched from Reyataz/norvir to Isentress 10/10
8/10: CD4: 731 CD4%: 40 CD8: 866
Diagnosed Sept. 2002 started meds May 2005.

 


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