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Author Topic: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach  (Read 148113 times)

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Offline Cosmicdancer

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  • Posts: 150
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #200 on: October 25, 2011, 08:09:44 PM »
Yes, Geobee, there's more info on this from Sangamo's presentation at a teleconference last Friday.  There's a somewhat lengthy transcript here.

http://www.investorvillage.com/smbd.asp?mb=1933&mn=42641&pt=msg&mid=11079955
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 AlexMerida

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #201 on: November 07, 2011, 07:16:18 PM »
can we  do something... in order to move cure-related research  forward as quickly as possible
We have to organize and give money to the researchers in order to catalyze the new promising therapies.. watch the work of abzyme form Professor Sudhir and the work of prof Loyter with the mix. They are the only one who have succeeded in controlling and eradicating HIV but they need dollars and the big pharmacy...we are the only interested. We do not have much time
As as community we need to stay involved ……
The benefits we have in our  life today  with ARV are because people took risks
I am totally new in these matters,  I jus have been diagnosed and about to start ARV,  and my friends always tell me that I am new and with time I will get used and after all I have my meds for sure that there is nothing to worried  about. But what about the rest of the world….more than halve of the polulation do not have acces to HIV drugs.
It is been 30 years but I do not think that all those year we have the conciseness about that years have passed but I do not think that we have struggled a real  battle it seem more like we are just pretending that we were fighting against HIV.
Friend always tell me that the cure will be in 20 o more and maybe it will be like cancer
Does anyone know the work of Zachary Benett for Abzyme
I contact Yissum the company who will commercialize the inventor  of Dr. Loyter and they told me that they are working on that..in fact de do not have any pharma interested.
so it is been 30 years and is time to believe. Or more accurately it is time to do real work
the  government has done ist part but what about us?
Many people are in the comfort area...but I  would ask them what can you give if you have the chance to be one day free of HIV..it  is possible but we have to catalyze it

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #202 on: November 14, 2011, 06:46:53 PM »
This is about a month old, a Paula Cannon interview from NBC LA.  She speaks so knowledgably, confidently -- such an inspiration!  Not much "new" news here, but it made me feel that one day this treatment is going to work.  

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

http://www.nbclosangeles.com/video/#!/on-air/as-seen-on/The-Fight-Against-HIV-AIDS-Goes-On/132119743
« Last Edit: November 14, 2011, 06:48:31 PM by geobee »

Offline TonyDewitt

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #203 on: December 29, 2011, 05:21:56 PM »
Sangamo's clinical trial on T-cells treated with ZFP's seems very promising, and appears to be the on-ramp for Paula Cannon's work on stem cells treated with ZFP's. If she can get the government to allow a clinical trail for that, we might be looking at the end of AIDS, if not the end of HIV. Apparently the funding structure in California requires that any candidate treatment be within four years of going to clinical trials, so the pressure is certainly on to get candidate treatments into clinical trails. Someone mentioned earlier Sudhir Paul's work with Abzyme Research Foundation, again very brilliant work, worth mentioning because these two avenues seem to be the best bets for saving lives from HIV. Maybe someday in the future we will see people treated with a combination of therapies.

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #204 on: December 29, 2011, 06:35:23 PM »
She has shown that ZFN-treated stem cells have eliminated HIV in humanized mice.  I also think that the ZFN-treated T Cells might work.  Sangamo's currently expanded the number of recruiting sites to find heterozygotes (I got myself tested and wasn't).  The "Trenton" patient (a heterozygote) went UD (at least temporarily, I don't know the longer term data) and they are trying to replicate that.  They are also preparing another trial to encourage the uptake of treated T Cells in non-heterozygotes.  From what I've read, this second trial will require a resubmittal by Sangamo -- they can't just tack it on to their existing trial.  From what I gather it also involves suppressing one's own T-Cells to give the newly expanding cells "space".   I haven't seen any recruitment for this second trial yet but expect it will be begin in the second half of 2012.  That's just a guess, though.
« Last Edit: December 29, 2011, 06:42:20 PM by geobee »

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #205 on: December 30, 2011, 03:05:03 PM »
Your day need a lift?

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

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

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

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

http://www.cenveomobile.com/issue/49332/15

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #206 on: January 09, 2012, 11:37:11 AM »
Here's today's press release about the two new trials from Sangamo.  The first (SB-728-902) is the Phase II trial of 20 heterozygotes "Cohort 5".  The second (SB-728-1101) is the Phase 1/2 trial of at least 9 patients whose T-Cells are reduced with Cytoxan.  In theory, this will give room for the newly-injected modified cells to expand and engraft. 

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

Here's the link to the PR:

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

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

"Many people taking cyclophosphamide do have serious side effects. Side-effects include chemotherapy-induced nausea and vomiting (CINV), bone marrow suppression, stomach ache, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, and lethargy. Hemorrhagic cystitis is a frequent complication, but this is prevented by adequate fluid intake and Mesna (sodium 2-mercaptoethane sulfonate). Mesna is a sulfhydryl donor and binds acrolein.
 
Cyclophosphamide is itself carcinogenic, potentially causing transitional cell carcinoma of the bladder as a long-term complication. It can lower the body's ability to fight an infection. It can cause temporary or (rarely) permanent sterility. A serious potential side-effect is Acute Myeloid Leukemia, referred to as secondary AML, due to it occurring secondarily to the primary disease being treated. The risk may be dependent on dose and a number of other factors, including the condition being treated, other agents or treatment modalities used (including radiotherapy), treatment intensity and length of treatment. For some regimens it is a very rare occurrence. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) seems to carry an AML risk of less than 1/2000th, with some studies even finding no increased risk compared to the background population. Other treatment regimens involving higher doses may carry risks of 1-2% or higher, depending on regimen. Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After 9 years, the risk has fallen to the level of the regular population. When AML occurs, it is often preceded by a Myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML."
« Last Edit: January 09, 2012, 05:27:52 PM by geobee »

Offline surf18

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #207 on: January 09, 2012, 07:53:38 PM »
that sounds horrid!

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #208 on: January 12, 2012, 07:09:44 PM »
Yeah, it does sound horrid.  All depends though on the dosing.  In more news, here's the transcript of Sangamo's press conference today with CEO Ed Lanphier.  Not much new news, but interesting nonetheless. 

http://seekingalpha.com/article/319266-sangamo-biosciences-ceo-presents-at-the-30th-annual-j-p-morgan-healthcare-conference-transcript?source=yahoo

Offline Mycen

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #209 on: January 13, 2012, 09:28:30 AM »
Thanks for the update, news has been pretty dry on hiv research.

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #210 on: January 13, 2012, 04:48:15 PM »
I think that Sangamo has not been trumpeting the news on HIV because they got burned by the diabetic neuropathy trial last year.  But these two trials that will soon be underway are very big deals. In 2012 we will know if they can give a functional cure to heterozygotes.  If they can that is a game changer. It also means they can probably do the same for the rest of us.  Huge.

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

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

Sorry for any fat fingering. On my phone.


Offline lmdo

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  • 35 years old
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #211 on: January 16, 2012, 05:44:37 AM »
True Mycen, new promising research news has been scarce. Fingers crossed still.
 :D

Offline emeraldize

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #212 on: January 31, 2012, 04:46:42 PM »
http://www.youtube.com/watch?v=1FejpwZZfGM


Bloomberg report on Sangamo. Stock's jumping.

Offline contagion

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #213 on: January 31, 2012, 05:22:56 PM »
The video says results are to be expected end of this month  - I presume Feb 2012 ? What results though?
I have a t-shirt with my t-cells on it.

Offline emeraldize

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #214 on: January 31, 2012, 08:56:27 PM »
This adds a little more, but not the exact meetings nor dates for announcements. http://investor.sangamo.com/releasedetail.cfm?ReleaseID=637760

Offline Cosmicdancer

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #215 on: January 31, 2012, 09:10:05 PM »
That video clip is about a year old, so she's talking about the phase 1 results that were going to come out in 2011.  If you look at the stock prices they showed, they are from the end of 2010.  Since then, prices have gone down, although they are creeping back up. 
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 emeraldize

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #216 on: January 31, 2012, 09:17:05 PM »
CD: Thanks for pointing that out -- I'll look into it. A friend sent it to me today stating it was freshly posted. Em

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

Nope, it's current. I've reposted the same link here as in the previous post. http://www.marketwatch.com/investing/stock/sgmo
« Last Edit: January 31, 2012, 09:32:40 PM by emeraldize »

Offline contagion

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #217 on: January 31, 2012, 10:31:34 PM »
I'm excited about this trial...though they wish they had some kind of timeline. I would line up to enroll in Phase 3!
I have a t-shirt with my t-cells on it.

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #218 on: February 09, 2012, 12:40:28 AM »
Sangamo has started dosing some of the heterozygotes.  They haven't yet started dosing for the Cytoxan trial.  At CROI they will present more data from last year's trials (not these trials). 

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

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


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

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

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

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

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

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

« Last Edit: February 09, 2012, 12:45:32 AM by geobee »

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #219 on: February 15, 2012, 11:49:22 AM »
Great article in Scientific American by Carl June and Bruce Levine -- well worth the read.

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


Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #220 on: February 15, 2012, 12:40:16 PM »
Really good article.  Covers some of the same ground as has been discussed here at length, but for anyone wanting perspective on this soon to be game changing technology, it's worth a read.

The last line is encouraging and says a lot:

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

Beware Romanians bearing strange gifts

Offline Pepino2

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  • Facial wasting need not be...Teach PMMA!
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #221 on: February 17, 2012, 06:26:36 PM »
big news yesterday.  president and CEO of sangamo states the following at the leerink health investment banker presentation.  SGMO stock price pops 27%.

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


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

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

:)

Offline contagion

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #222 on: February 19, 2012, 02:14:50 PM »
From IV board
]-->A: Speak first to level, del 32 heterozygote in 12-15% biallelically modified T cells. That is a signal. Can achieve in del 32. Think much higher levels in enhanced engraftment. Think works in all patients, not just heterozygotes. What drives us, viral load, end points, what is functional cure.

I'm not understanding much of that...but I like the keywords in your post!
I have a t-shirt with my t-cells on it.

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #223 on: February 19, 2012, 07:33:33 PM »
This run up in price on no "new" news making me think they might be a take over candidate. Hope big pharma doesn't buy them and put their HIV work on the back burner.  Probably just being paranoid.

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #224 on: February 29, 2012, 11:57:01 AM »
Here's an article on Daily Kos re: Sangamo's trials:

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

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

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

Here's the poz story:

March 2012


Helping to Find a Cure for AIDS

by Bill Strubbe

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Find and join other studies
For comprehensive trial info, go to:
clinicaltrials.gov
aidsinfo.nih.gov
actgnetwork.org

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #225 on: March 02, 2012, 01:55:59 PM »
So I called Quest to inquire about the trial.  It was interesting.  The "Trenton" patient (the one who went UD in the first trial) as a) heterozygous b) newly infected c) had high T-cells and d) had a low adenovirus antibody titer.

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

So they are looking, in these two trials, to replicate the Trenton patient.  First trial: get heterozygotes.  Second trial:  look for people that have T-Cells above 600, infected in the last 5 years, and low adenovirus antibodies.

Offline Dr.Strangelove

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #226 on: March 03, 2012, 02:37:06 PM »
These are really great news.
Thanks for keeping us updated.

Offline ichigo_kun

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #227 on: March 09, 2012, 05:35:40 PM »
Pathway to a Cure: Positive Results Continue for Sangamo’s CCR5 Gene Therapy
by Tim Horn
Genetically modifying CD4 cells to knock out the CCR5 coreceptor resulted in significant CD4 count gains and notable viral load reductions while off antiretroviral (ARV) therapy, according to new data from a clinical trial of Sangamo Biosciences’ zinc finger nuclease (ZFN) therapy SB-728-T, reported Thursday, March 8, at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle.

Background

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

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

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

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

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

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

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

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

CROI Update

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

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

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

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

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

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

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

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

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

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

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

In conclusion, Tebas said that data from these studies involving discordant responders and immune responders is “promising and warrants further evaluation. Further clinical development of SB-728-T,” he added, “will aim to maximize patient exposure to CCR5 bi-allelic modified CD4 cells in two ongoing clinical trials.”

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #228 on: March 19, 2012, 11:32:37 AM »
So I went and got myself screened for the second Sangamo trial (I screened for the first and wasn't a heterozygote).  Most people are failing the screening because they have a high level of the adenovirus 5 titer.  Quest said that this titer is seasonal -- if you've been around kids a lot you probably have a higher level.  Results take about a month (first they check T-Cells / VL.  If that's OK for the trial, they go on on to test the A5 antibody).

Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #229 on: March 22, 2012, 09:07:56 AM »
It sounds like adding Chemo didn't help.  Hopefully the purification step is added in future trials talked about in this article here:

http://www.aidsbeacon.com/news/2012/03/19/chemotherapy-plus-stem-cell-transplantation-is-not-sufficient-to-cure-hiv-aids-croi-2012/

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #230 on: March 22, 2012, 11:42:05 AM »
Yeah, but your link has nothing to do with the current Zinc Fingers/Sangamo phase II trial. Scared me for a minute... :o Zinc Fingers is the topic of this tread. Some info on the current Sangamo trials should be coming out in a few months...July?

Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #231 on: March 22, 2012, 04:30:39 PM »
Yeah, but your link has nothing to do with the current Zinc Fingers/Sangamo phase II trial. Scared me for a minute... :o Zinc Fingers is the topic of this tread. Some info on the current Sangamo trials should be coming out in a few months...July?

Ah, ok that's good, whoops

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #232 on: March 22, 2012, 05:08:58 PM »
Yeah, that was a different trial.  Didn't involve resistant stem-cells treated with ZFNS.

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

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


Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #233 on: March 24, 2012, 06:11:16 PM »
Geobee, don't think the CCR5 gene modification is a shot in the dark. BUT, I don't think the current trials using CD4s is going to get us to a functional cure, but somehow I do see it as a posible end game for AIDS, although perhaps a yearly treatment will be envolved. If the Sangamo people start using STEM CELLS and modify something in the range of 90%, then THAT will be a game changer. If I were a betting man, I'd bet on Calimmune with its RNAi to do the trick for a functional cure...RNAi seems to have more knock-out power then Zinc Fingers. Although I'm still praying for Sangamo to anounce breakthroughs this summer/fall.

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

« Last Edit: March 24, 2012, 06:25:48 PM by Tadeys »

Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #234 on: March 24, 2012, 06:58:36 PM »
Geobee, don't think the CCR5 gene modification is a shot in the dark. BUT, I don't think the current trials using CD4s is going to get us to a functional cure, but somehow I do see it as a posible end game for AIDS, although perhaps a yearly treatment will be envolved. If the Sangamo people start using STEM CELLS and modify something in the range of 90%, then THAT will be a game changer. If I were a betting man, I'd bet on Calimmune with its RNAi to do the trick for a functional cure...RNAi seems to have more knock-out power then Zinc Fingers. Although I'm still praying for Sangamo to anounce breakthroughs this summer/fall.

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

Interesting, had to google Calimmune thanks.

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

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

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

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

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

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

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

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

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

Hell, maybe we can do BOTH trials at the same time?  You can already over lap others we'll see what they say.
« Last Edit: March 24, 2012, 07:15:06 PM by JazJon »

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #235 on: March 24, 2012, 07:48:09 PM »
I'd do Callimune. And I would also do Zinc Fingers Stem Cells (its in their pipeline). Callimune has David Baltimore(google). I 'd do everything that looks promising. I think Callimune is going to start with stem cells...right? I like permanence. You can't get that with cd4s.

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

The following is in another thread, but since you mentioned clinical trials ans I mentioned Baltimore I need to go further: David Baltimore and Balasz came up with vectored immunophrophylaxis about a year ago. Basically, using a vector, muscle cells start pumping out broad neutralyzing antibodies. Clinical trials MIGHT start this year. They have this as Preventive (yes!) and alternative to clasical vaccinology but I think it can also be used as a therapeutic vaccine. Its simple really, by getting the body to produce the same
antibodies that elite controllers use MIGHT make me into an elite controller and thus
 a functional cure. If I could, Id sign up for this trial also.  ; ;)

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #236 on: March 24, 2012, 09:37:26 PM »
Hey Tadeys --

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

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

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

George

PS:  4 mos in, huh?  Hope it's going well.  I've been poz for about 3 years. Anyway, the first year was a blur -- but life is good now.  It gets better.

Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #237 on: March 24, 2012, 10:07:55 PM »
Awesome, yeah I've only been poz for 3 weeks, and I already dived into a clinical trials.   I'll do any and all promising trials that sounds promising, sign me up.  I'm at Quest in SF too by the way :)

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #238 on: March 25, 2012, 05:26:33 AM »
These past few months HAVE been a blur. What has kept me going is news on research.There are SOOOO many things out there for HIV, with about a dozen or so posible cures--at least in pre-clinicals and a few clinicals. If only the whole process from conception to Rx were faster. Hope the Hagan bill passes to speed things up a bit. ;)
« Last Edit: March 25, 2012, 05:30:11 AM by Tadeys »

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #239 on: March 29, 2012, 01:34:04 AM »
RICHMOND, Calif., March 28, 2012 /PRNewswire/ --Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that Edward Lanphier, Sangamo's president and CEO, will provide an update on the progress of Sangamo's ZFP Therapeutic® development programs and an overview of the company's business strategy at 8:40 am ET on Wednesday, April 4, 2012, at the 11th Annual Needham Healthcare Conference which will be held in New York City.
The presentation will be webcast live and may be accessed via a link on the Sangamo BioSciences website in the Investor Relations section http://investor.sangamo.com/index.cfm under Events and Presentations. The presentation will be archived on the Sangamo website for two weeks after the event.

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

Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #240 on: March 29, 2012, 01:36:23 AM »
RICHMOND, Calif., March 28, 2012 /PRNewswire/ --Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that Edward Lanphier, Sangamo's president and CEO, will provide an update on the progress of Sangamo's ZFP Therapeutic® development programs and an overview of the company's business strategy at 8:40 am ET on Wednesday, April 4, 2012, at the 11th Annual Needham Healthcare Conference which will be held in New York City.
The presentation will be webcast live and may be accessed via a link on the Sangamo BioSciences website in the Investor Relations section http://investor.sangamo.com/index.cfm under Events and Presentations. The presentation will be archived on the Sangamo website for two weeks after the event.

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

Exciting, let's hope there is good news/progress. 

Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #241 on: April 04, 2012, 04:26:44 AM »
Here's the conference we'll be able to listen to in a few hours. (4 hours as of this post)   I did a test, it seems this stream only works using Internet Explorer.   I tried Firefox and Chrome and it didn't work.

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

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

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



Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #242 on: April 04, 2012, 09:38:14 PM »
Here's the conference we'll be able to listen to in a few hours. (4 hours as of this post)   I did a test, it seems this stream only works using Internet Explorer.   I tried Firefox and Chrome and it didn't work.

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

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

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


The last few minutes of Q & A are very interesting.  (sounds promising!)

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #243 on: April 05, 2012, 05:53:31 PM »
Hey JazJon --

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

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

George

Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #244 on: April 05, 2012, 07:11:47 PM »
Hey JazJon --

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

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

George

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

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

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

Progress marches on...........

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #245 on: April 10, 2012, 12:37:35 PM »
So I went to Quest to find out more about the CalImmune study.  There will be 3 cohorts --

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

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

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

Other thoughts --

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

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

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

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

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

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

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

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

But, if it works, will this be a therapy for all people?  Can we really imagine a scenario where people in all parts of the world extract their blood through apheresis
, ship it to some lab, get some chemo, and then get reinfused?  I can imagine it.  Yes, there will be cost and delivery hurdles -- but taking meds forever is not going to work either.  Death rates have dropped off because of the cocktail, but more and more people are living with HIV every year.  If a solution is known to cure people, the manufacturing and distribution process will improve driving costs down and making it widely available to all.
« Last Edit: April 10, 2012, 12:42:27 PM by geobee »

Offline xman

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #246 on: April 10, 2012, 02:50:48 PM »
it is indeed possible that one virion is not capable to reseed the entire infection. if we consider that a certain viral load is necessary for transmission perhaps even in an established infection a minimum amount of virus is essential to keep the population alive. it is only a theory but with luck not every virion must destroyed to be cured.
sign the petition launched by the aids policy project addressed to the nih aimed to increase the money needed to find the cure:

http://www.aidspolicyproject.org/petition_for_the_nih

we can make a difference and we need to fight. please support them! it doesn't cost you anything. they need it now more than ever!

Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #247 on: April 10, 2012, 09:03:33 PM »
Excellent update geobee, thanks for the very informative breakdown.  I'm looking forward to being part of these new trials.

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #248 on: April 11, 2012, 01:04:38 AM »
Sure hope you're right X-Man -- that we don't have to get at every virion -- that we can somehow get at most of them and let our immune system do the rest.  I thought the article you posted (thank you) re: the small molecule formulations of Reyataz and Truvada was really interesting.  If we could find drugs that would effectively go after the reservoirs that would sure be a game changer.
« Last Edit: April 11, 2012, 01:14:14 AM by geobee »

Offline Dr.Strangelove

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #249 on: April 11, 2012, 11:09:38 PM »
Quote
Head scratcher:  I can't figure out why all the patients receiving the modified T-Cells in the first trial didn't go UD.  They all had some immune T-Cells, right?  Why didn't HIV wipe out the non-immune T-Cells and leave the immune T-Cells?  Is it because the body keeps producing the non-immune cells?  If so, can they just increase the ratio of immune cells (which fight HIV) to non-immune cells, will that be enough to overwhelm the amount of virus in the body?

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

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

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

Quote
But, if it works, will this be a therapy for all people?  Can we really imagine a scenario where people in all parts of the world extract their blood through apheresis, ship it to some lab, get some chemo, and then get reinfused?  I can imagine it.  Yes, there will be cost and delivery hurdles -- but taking meds forever is not going to work either. If a solution is known to cure people, the manufacturing and distribution process will improve driving costs down and making it widely available to all.
After my initial excitement, I don't see this approach as 'the' solution anymore. Surely, the ex-vivo method that Sangamo is exploring now is just a first step. I don't think it will ever be widely applied. It's just too complicated of a procedure and I don't see how they can make it much more cheaper. It's not like a drug, that can easily be mass produced. Also, I don't think their current method will be able to reproduce the results of the Berlin patient.
Maybe it will be a solution for people who have no other option.
I am more optimistic about the modified stem cells. This would be a one-time procedure.
Anyway, these are my thoughts.
 
« Last Edit: April 11, 2012, 11:14:20 PM by Dr.Strangelove »

 


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