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Author Topic: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach  (Read 153605 times)

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Offline oh-no

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #400 on: July 05, 2013, 08:33:56 AM »
Actually the fact that different methods are used means that different outcomes can be achieved. The study referred to used RNA ribozyme to treat the stem cells. Many scientist in the field no longer believe that using a ribozyme on its own can provide the long term benefits required to produce a HIV cure.

Yes different methods lead to different success of viral suppression.
But I don't see how this method could effect engraftment.

Cells could be resistant to virus, but as long as they die shortly after infusion therapeutic goal its not reached.

 This is a main difficulty which need to be solved.

 For the experiment it even doesn't meter which gene those cells have as long as this gene doesn't affect proliferation.
It could be just mark. The problem is that any infused cells don't live long enough.

 As I understand this is because main proliferation and production of cells take place in the marrow bone, not in the blood.
Blood doesn't reproduce itself effectively, this is the function of marrow bone.
The majority of progenitor cells are there, so infusion always has only temporary effect no meter which genes scientists have changed.


« Last Edit: July 05, 2013, 08:42:02 AM by oh-no »

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #401 on: July 05, 2013, 10:24:27 AM »
Oh no: I think all of these companies have stem cell clinical trials coming up. This should take care of cells dying off.

There is a medication used to oust stem cells from bone-marrow. If you go onto the Calimmune thread you can read up on that. One of the patients of the callimune clinical trial commented on the said thread about the side effects of that particular drug...bone pain if I remember correctly.
 
Believe me, they have most of these things figured out.
Cheers

Offline Hoyland

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #402 on: July 05, 2013, 10:37:37 AM »
Quote
Yes different methods lead to different success of viral suppression.
But I don't see how this method could effect engraftment.

Cells could be resistant to virus, but as long as they die shortly after infusion therapeutic goal its not reached.

Different approaches allow for different delivery/transfection vectors. The case of OZ1 the team used a retrovirus as the vector. Calimmune uses a lentiviral vector which is more efficient.

If you watched the video you will see that, in the case of the CoH trial, patients who received the treatment still have modified cells in their systems years after the  procedure. So the notion that all the modified cells die soon after being re-introduced to the patient is not correct. The researchers now need to get the transfection rate high enough for the new cells replicate in sufficient numbers to overcome the virus. This is the work that CoH is currently conducing.

The above does not mean that transfection is not an issue - it is. However, rates are improving all the time as vectors are being refined and at some point - maybe in this Calimmune trial - the rate will be sufficient for clinical success.


Offline oh-no

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #403 on: July 05, 2013, 12:19:06 PM »
Tadeys, I talk about stem cells. OZ1 is the stem cell project.
Long live it its not what we can expect from T-lymphocytes.

« Last Edit: July 05, 2013, 12:26:16 PM by oh-no »

Offline oh-no

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #404 on: July 05, 2013, 12:54:05 PM »
Hoyland, is there an information about rate of modified cells which last year's after infusion?
OZ1 also last but only 7%
Does CoH methods have better results?

I suggest methods does not effect proliferation significant.

Offline Ann

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #405 on: July 05, 2013, 01:07:06 PM »
Hi oh-no, welcome to the forums.

Don't take this the wrong way, but I have to wonder why you're so fixated on reading about a cure when you're so newly diagnosed.

I would think your time would be better spent in understanding the basics of hiv. Going by your response in the What do you think of this comment about HIV by porn actor Brent Corrigan? thread, you still have a lot to learn about living with hiv.

We're glad you're here and we want you to learn about living with hiv - because that's what you need to be doing first and foremost. A cure is still a long way off.

I hope you will consider starting a thread in the I Just Tested Poz forum where you can introduce yourself and tell us a bit more about how you're doing. For example, what are you numbers and are you on meds yet or are you considering your treatment options? (Please don't answer those questions in this thread - start one in Just Tested. Thanks.)

Ann
Condoms are a girl's best friend

Condom and Lube Info  



"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

Offline Hoyland

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #406 on: July 05, 2013, 09:29:08 PM »
Oh-no, this is the paper that was published in journal Science Translational Medicine, a journal published by the American Association for the Advancement of Science, which describes the work done at the CoH.

You have to remember that this paper is now three years old and the patients referred to where treated in 2008. Yes, there was only a very low level of modified cell retained after the first four weeks but twenty four months out, low levels of cell retention were still measured. As the video says, one patient of the four treated has increasing levels of modified cells to this day.

Since 2008, improvement in engraftment techniques has been a major focus of researchers and the main reason why it has taken so long to get more clinical trials started. The current Calimmune study will give the scientific community the chance to see just how far this process has come. I believe the CoH team  are now confident that they are near to getting a clinically significant level engraftment to take place and will be in a position to enrol patients in a new trial if they getting the funding to do so.

The UC Davis team, which has pre-clinical work showing higher levels of engraftment, failed in its bid to obtain funding from the CIRM and I am not sure where this program is going.

You should watch out for a team led by Prof Ben Berkhout in the Netherlands. His team is working on a slightly different approach to Calimmune but still using viral vectors. They may be in the clinic in the next six to twelve months.

Offline Hoyland

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Offline 1in1000000

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #408 on: July 10, 2013, 07:29:27 PM »
It seems, current genetic studies are aimed to repeat the effect of entry inhibitors.
CCR5 viruses are more common, but virus can switch to CXCR4 after one mutation.
CXCR4 is important for haematopoiesis, disruption of CXCR4 will affect human health.

My conclusions based on
HIV Medicine 2012 by Hoffmann & Rocktroh
p. 96 Entry inhibitors

Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #409 on: September 10, 2013, 07:57:20 PM »
late breaker at ICAAC

Functional Control of Viremia in CCR5-Δ32 Heterozygous
(Δ32HZ) HIV+ Subjects Following Adoptive Transfer of Zinc Finger
Nuclease CCR5 Modifi ed Autologous CD4 T-cells (SB-728-T)
D. Ando1
, J. Lalezari2
, G. Blick3
, J. Rodriquez4
, R. Hsu5
, T. Hawkins6
, D. Parks7
, j.
Zeidan8
, R-P. Sekaly8
, S. Deeks9
; 1
Sangamo, Richmond, CA, 2
Quest, SF, CA, 3
CC,
Norwalk, CT, 4
OCMG, NPB, CA, 5
PC, NY, NY, 6
SWC, S Fe, NM, 7
CWCR, St.
Louis, MO, 8
VGTI, PSL, FL, 9
UCSF, SF, CA
Background: Expression of CCR5 by CD4 cells is necessary for productive R5
HIV infection. Biallelic KO of CCR5 in CD4 cells by SB-728-T is enhanced in
CCR5 Δ32HZ. This study was undertaken to assess the effect of SB-728-T on
Δ32HZ, following an earlier report of a SB-728-T-treated Δ32HZ whose VL
became undetectable (UD) at the end of a treatment interruption (TI). Methods:
Ten aviremic, HIV+, Δ32HZ on stable ART with CD4 counts >500/mL were
enrolled. SB-728-T was manufactured with a mean CCR5 modifi cation of 25.5%
(range 17.4-44%). Subjects received 16.2+4.2 (mean+SD) billion total cells (range
9.0-23.5). After infusion, subjects were followed for 8 wks and then underwent a 16
week TI. Results: Median duration of follow-up for all subjects is 305 days (range
70-365). Circulating total CD4 counts increased from baseline by 1156+601 cells/
mLat D28. Estimated biallelic modifi ed CD4 cells ranged from 5 to 14% of PBMC
CD4 cells at D28. Three subjects had X4/R5 at baseline and in 2 R5 subjects, TI
was terminated early per protocol due to high initial VL. One R5 subject recently
commenced TI. Of the 4 remaining R5 subjects, 1 showed no signifi cant VL
reduction from peak during TI. One subject had a 1-log VL reduction; and another
subject showed a persistent 1-log reduction from peak with a single UD VL before
resuming HAART. Both of these subjects had increased polyfunctional GAG T
cell responses. The 4th subject has UD VL persisting for 4 weeks following an
initial peak; TI is ongoing. The two subjects with UD VL during TI had low HIV
set points (VL 3-4000 copies/mL) and proviral DNA(<100 copies/106
 PBMC by
ddPCR). Conclusions: Adoptive transfer of SB-728-T in Δ32HZ resulted in VL
reductions from peak levels during TI in 3 of 4 subjects with 2 subjects having
UD levels, persisting in one subject for 4 weeks at the time of abstract submission.
Reductions in VL were associated with low baseline HIV reservoir, low HIV
setpoint, and increases in polyfunctional GAG T-cell responses. CCR5 knockout in
CD4 T cells by biallelic ZFN-mediated CCR5 modifi cation may lead to functional
control of R5 HIV infection in a subset of CCR5 delta32 HZ individuals.

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #410 on: September 10, 2013, 09:04:06 PM »
Hmmmmmm......
Beware Romanians bearing strange gifts

Offline Tadeys

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  • Posts: 159
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #411 on: September 10, 2013, 09:28:54 PM »
"The 4th subject has UD VL persisting for 4 weeks following an
initial peak; TI is on going."   

Does anybody know how much a person's VL would have peaked after 4 weeks of TI under non-sangamo Treatment? Correct me if I am wrong but, does'nt VL peak to pre-Treatment levels by 8 weeks?

Offline sfpvguy41

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #412 on: September 12, 2013, 05:43:46 PM »
Here's the press release.  I am trying to understand (and would love to know from others if they see it) why they believe some in this study of subjects with the Delta-32 heterozygote exhibit the ability to maintain undetectable VL and others not.

Nevertheless the ability to report they have attained viremic control in anyone is pretty amazing and I believe a big step.


http://www.heraldonline.com/2013/09/12/5203805/sangamo-biosciences-announces.html
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.

Offline Dr.Strangelove

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #413 on: September 13, 2013, 08:44:44 PM »
Not sure this answers your question but I think one of the reasons why some patients went UD and others did not is their initial VL:

Quote
The two subjects with UD VL during TI had low HIV set points (VL 3-4000 copies/mL)

To go undetectable starting from 4000 copies/ml is a lot easier than when your initial viral load is in the tens of thousands or hundreds of thousands.

Offline Tadeys

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  • Posts: 159
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #414 on: October 28, 2013, 08:14:48 AM »
Reduction of Viral Load at or Below Limit of Detection Ongoing at 14 Weeks
 
Additional Presentations of Preclinical Data at Annual Meeting of European Society of Gene and Cell Therapy (ESGCT)
 
RICHMOND, Calif., Oct. 28, 2013 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today the presentation of new data demonstrating sustained control of HIV viral load (VL) at or below the limit of detection for 14 weeks (at last measurement) in an SB-728-T- treated HIV-infected subject who was not on antiretroviral therapy (ART). The CCR5 delta-32 heterozygote subject is enrolled in Sangamo's clinical trial (SB-728-902 Cohort 5) and, as part of the clinical trial protocol, is undergoing an ART treatment interruption (TI), which is ongoing.

http://online.wsj.com/article/PR-CO-20131028-902967.html

Offline Skydrake

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #415 on: October 28, 2013, 03:38:05 PM »
....new data demonstrating sustained control of HIV viral load (VL) at or below the limit of detection for 14 weeks (at last measurement) in an SB-728-T- treated HIV-infected subject who was not on antiretroviral therapy (ART). The CCR5 delta-32 heterozygote subject is enrolled in Sangamo's clinical trial (SB-728-902 Cohort 5) and, as part of the clinical trial protocol, is undergoing an ART treatment interruption (TI), which is ongoing.

Was or was not this subjet on ART?
How could be possibile to perform an ART treatment interruption in a subjet who was NOT on ART?

« Last Edit: October 28, 2013, 03:43:49 PM by Skydrake »

Offline GoForIt

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  • Posts: 95
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #416 on: October 28, 2013, 03:49:52 PM »
Pretty easy to understand....They are saying that this person took a TI during the phase of this study.  Not that this person NEVER took ART and is taking a TI...that doesn't make any sense....

It's nice that they did achieve UD for some weeks and all but only in 1 out of the 10 subjects? Only 6 were evaluable....and only one maintained the UD. That is not very good.  Hopefully they can learn something from this one person.
« Last Edit: October 28, 2013, 03:52:37 PM by GoForIt »
08/09/2013   Diagnosed WB positive
08/20/2013   CD4-506(28%)  VL-10,800
09/12/2013   CD4-391(28%)  VL-14,900
09/17/2013   Start ART (Truvada & Tivicay)
10/11/2013   CD4-377(26%)  VL-UD
12/20/2013   CD4-590(??%)  VL-UD
03/18/2014   CD4-660(29%)  VL-UD
07/22/2014   CD4-613(29%)  VL-UD
08/01/2014    Start TAF Clinical Trial

Offline Tadeys

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  • Posts: 159
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #417 on: October 28, 2013, 04:25:38 PM »
Do not think its that bad if one considers that the viral load correlates with the percentage of grafted CD4s...thats what I read this morning. So it is a matter of tweaking the technology OR going through a series of more treatments/doses with the current technology. Personally, I would do the process 20 times if it got me off meds for good.

Anyways, I always had my money with Callimune's technology, not zinc fingers. I am surprised that it even worked with one person...although one cant really call it victory at 14 weeks; Id like to see this person UD for a least 52 weeks. But 14 weeks IS a good sign.

Gene therapy is the most avanced technology we have in terms of a cure now that the viral load got a lot harder to eliminate with the Shock and Kill approach.

Fingers crossed with Callimmune and City of Hope's trials...


Offline bmancanfly

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  • Medicare For All !
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #419 on: December 06, 2013, 08:50:48 AM »
that link doesn't work.
"The trouble with the world is that the stupid are cocksure and the intelligent are full of doubt."

 Bertrand Russell


Offline sfpvguy41

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  • Posts: 115
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #421 on: December 06, 2013, 02:57:13 PM »
Here's how I summarize this great news on HIV: Sangamo today announced further progress from actual clinical trials on the path to a functional cure of HIV (disease controlled without needing meds).... "the data that have been generated in the course of the clinical investigation of this novel therapy on reductions in viral load and the levels of viral reservoir, as well as the increases in total CD4 cells, demonstrate that a single SB-728-T treatment has the unique ability to enable sustained immunological functional control of HIV in the absence of ART."

Essentially they have announced that by pretreating with an existing drug, Cytoxan (which knocks out CD4s), they have learned how to engraft enough modified CD4 cells to modify the immune system sufficiently in certain types of patients (CCR5 heterozygotes) so it can stave off HIV without needing meds, similar to how the Berlin patient was cured. Now they have to prove this in other cases using higher engraftments, and it will have to go through Phase 3 trials and come to market, so it's not something we'll see available for years.

There's a lot to this announcement, but it's a positive step. 
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.

Offline dico

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  • Posts: 88
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #422 on: February 22, 2014, 06:57:49 AM »
This thread was very interesting. Unfortunately it wasn't updated since December. Any news about this Sangamo trial and comparison with Calimmune ?

I want to restart this topic and know your thoughts (especially Hoyland).

I think there are 2 advanced approaches (clinical trials) as of 2014 :
- Sangamo/City of Hope with ZFN and cytoxan (for both CD4 and HSC) : beginning in 2014
- Calimmune/Benitech with ddRNAi and busulfan (for both CD4 and HSC) : beginning in 2014 too (with buslfan)

Why are these approaches important ? As the vaccine approach failed during the past 30 years. There is not a single vaccine nor a drug that have cured even a single patient. So, if one of the two above approaches succeeds, we can hope to have a functional cure for a subset of patients in less than 10 years.

The subset of patients are, I think, healthy youngs with no other disease (no HBV / HCV) and treated early for at least 2 years (i.e. with the lowest viral reservoirs) and with documented low viral set points (less than 5000 copies/ml ?). This subsent of patients are clearly a minority but what is important is that afterwards, the technique can be improved to cure others (like me as I have been late diagnosed and had at the beginning a high viral set point of more than 10,000 copies/ml).

I am more optimistic with the Calimmune trial as it has shown a higher engraftment of biallelic-modified CD4 according to studies and they have cleverly added an antifusion protein (C46).

I think it is possible to combine the Calimmune/Benitech method with that of Prof Ben Berkhout (inhibiting HIV proviral replication) and with a combination of Busulfan for HSC and Cytoxan for the CD4. I think both chimio will raise the engraftment to a maximum level of one third modified cells (which is not that high unfortunately) at the beginning and maybe more afterwards as the non-modified CD4 will die with treatment interruption.

So what are your thoughts ?
« Last Edit: February 22, 2014, 07:06:57 AM by dico »

Offline Hoyland

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  • Posts: 75
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #423 on: February 22, 2014, 09:35:29 PM »
Dico,

There is a third trial approved but not yet recruiting.

Busulfan and Gene Therapy After Frontline Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma
http://www.clinicaltrials.gov/ct2/show/NCT01961063?term=city+AND+hope+AND+HIV&rank=3

The City of Hope clinical data from four years ago and the Sangamo clinical data are the only data available for these gene therapies in humans. The Calimmune pre-clinical data is very positive (one more pre-clinical publication to be released) but it is pre-clinical and therefore cannot be compared directly with the other two data sets. The Calimmune science looks good but, until we see some data coming out of the trail, I think it is too early to judge which of these approaches is likely to be the most efficacious.

I understand that Calimmune is already planning a second trial, which is a good sign that they are confident the results for this trial will be positive. The other thing about Calimmune is that they are not a government or educational facility nor do they have other treatments in the pipeline. Curing HIV is there entire raison d'etre. A failure for them is the end of the line and so I am sure their scientists are paddling like crazy to make Cal-1 work, or at least work out how to refine it so that it does work.

Offline Hoyland

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  • Posts: 75
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #424 on: February 22, 2014, 10:04:36 PM »
I should have added that the lead scientists or CEO for all of these trials are attending this roundtable event. Dr Zaia for Sangamo/CoH, Dr deGiusto CoH and Mr Breton Calimmune.

http://www.oxbridgebiotech.com/events/gene-therapy-risky-business/

Offline dico

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  • Posts: 88
Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #425 on: February 23, 2014, 02:21:52 AM »


I understand that Calimmune is already planning a second trial,

Hoyland,

Where did you find this info ?

Thanks

Offline Hoyland

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #426 on: February 23, 2014, 06:05:07 AM »
Dico, the following has been confirmed by other sources.

Quote
The therapy is currently in a Phase I/II clinical trial in California, and Calimmune plans to expand its clinical studies to other countries, including Australia, in the near term. Therapeutic Innovation is supporting work-up for the planned Australian trial.


http://www.therapeuticinnovation.com.au/About_Us/Latest_Projects/Calimmune_patient-focused_HIV_solutions_development.aspx

In terms of your question above about different types of individuals that can be treated, Calimmune's own publicity says:

Quote
Calimmune is also developing a rich product candidate pipeline to address the needs of different types of individuals at different states of HIV infection and with different levels of treatment experience.

Hope this helps.

Offline dico

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #427 on: February 23, 2014, 12:08:11 PM »
I contacted the ANRS, the equivalent of NAID but in France.

They confirmed they plan to test an anti-hiv gene therapy. They follow closely the Calimmune trial but they think this trial lacks ambition. They don't believe in the C46 approach of Calimmune but want to add 3 anti-HIV protein RNAi.

I actually found an English article speaking about that (the other ones are in French) :

http://www.catie.ca/en/treatmentupdate/treatmentupdate-196/hiv-cure-research/promise-genetic-therapy-hiv

Quote
Led by France’s premier scientific research agency, the ANRS (Agence nationale de recherches sur le sida et les hépatites virales), researchers in France, Austria, Germany, Italy and the U.S. are planning to conduct clinical trials of a gene therapy that has the potential to interfere with key HIV proteins (called Tat, Rev and Vif) and to also block the CCR5 receptor of cells. Such a multifaceted approach carries the possibility of not only protecting cells from the entry of HIV but also helping the immune system overcome the toxic effect of HIV’s proteins.

Offline dico

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #428 on: February 23, 2014, 12:18:56 PM »
It would have been better if all of them : Calimmune, ANRS, Prof Ben Berkhout, etc... collaborated together. But it seems there is a competition between them.

In the mail, the researcher told me that it was very difficult to have more knowledge of the Calimmune trial. As I understand, and when we read his mail between the lines, it seems that David Baltimore and his Calimmune company don't want to cooperate and share their knowledge with others.

I would hope we had more power to force them to work together.

Nevertheless,  I will write another mail to know when they plan their clinical trial in France.
And if some other guys know more about other clinical trials being planned around the world, feel free to share it to us.

Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #429 on: March 05, 2014, 11:10:46 PM »
Happy to see that this study is published in NEJM

http://www.nejm.org/doi/full/10.1056/NEJMoa1300662?query=featured_home

The results published are much earlier in the trial. SGMO has moved a lot forward.
This presentation makes a nice summary.
http://wsw.com/webcast/cowen16/SGMO/

In the heterozygous cohort, one patient stays undetectable without HART for more than 20 weeks and ongoing.

The company is now trying to enhance the engraftment and going to release new data at croi 2014:

Cyclophosphamide Enhances SB-728-T Engraftment To Levels Associated With HIV-RNA Control

The company is also going to start a trial middle this year using stem cells! And their new technology allows over 50% disruption of both CCR5 gene.

Looking forward to it :-)
« Last Edit: March 05, 2014, 11:20:26 PM by greenbean »

Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #430 on: March 05, 2014, 11:16:32 PM »

Offline dico

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #431 on: March 06, 2014, 02:08:44 AM »


The company is also going to start a trial middle this year using stem cells! And their new technology allows over 50% disruption of both CCR5 gene.



Are you really sure about that ?? I never read any articles telling such a thing.

Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #432 on: March 06, 2014, 02:34:33 AM »
Are you really sure about that ?? I never read any articles telling such a thing.


For the stem cell trial planned in the middle of this year. look at the slides:
http://wsw.com/webcast/cowen16/SGMO/  (at the end)

New method for gene disruption using mRNA:
http://at.pscdn.net/008/00240/symposia/2013/paula_cannon/


Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #433 on: March 06, 2014, 08:01:08 AM »
Looks like SGMO is getting a massive amount of attention based on their presentation yesterday at CROI.  The CEO talks about their HIV efforts and the stock goes up 25%.  Getting press in the New England Journal of Medicine and a feature on CBS News doesn't seem to have hurt either.  Hmmm...
« Last Edit: March 06, 2014, 08:05:11 AM by freewillie99 »
Beware Romanians bearing strange gifts

Offline dico

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #434 on: March 06, 2014, 03:15:48 PM »

For the stem cell trial planned in the middle of this year. look at the slides:
http://wsw.com/webcast/cowen16/SGMO/  (at the end)

New method for gene disruption using mRNA:
http://at.pscdn.net/008/00240/symposia/2013/paula_cannon/

Yes but I don't see the 50% you were talking about...

Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #435 on: March 06, 2014, 03:33:22 PM »
Yes but I don't see the 50% you were talking about...

It is at the end of the presentation. If you can't find it here is another presentation using the same technology. They show that it can modify up to 80% of the stem cells (7:50) at large scale, which prompts their collaboration with biogen.

http://www.youtube.com/watch?v=Md9yAYJCtpQ
« Last Edit: March 06, 2014, 03:36:32 PM by greenbean »

Offline sfpvguy41

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #436 on: March 06, 2014, 10:01:38 PM »
Great news from Sangamo today at CROI:

1) pretreating with Cytoxan makes their treatment more effective
2) they have achieved functional control of HIV in one individual who has gone off treatment for 31 weeks.
3) they are trying delivery via mRNA rather than using a virus, which allows for retreatment


http://online.wsj.com/article/PR-CO-20140306-911981.html

A quote:
"The achievement of over 7 months of ongoing functional control of viral load without antiretroviral therapy and the progress that we are making in understanding how to best deploy this novel therapy are very exciting, " commented Gary Blick, M.D., AAHIVS, Medical & Research Director, CIRCLE CARE Center, who presented the data at CROI and is an investigator on both studies that were reported at the meeting. "The data that have been generated over the course of the clinical investigation of SB-728-T demonstrate immune reconstitution, enhanced survival of the zinc finger nuclease-modified T-cells in the presence of the virus and associated reductions in viral load and the levels of viral reservoir, all of which are necessary to provide functional control of the virus."

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.

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #437 on: April 13, 2014, 03:08:08 PM »
Really nice article.  Informative and encouraging.

http://aumag.org/wordpress/2014/04/11/editing-genes-for-a-cure/

Editing Genes for a Cure

Posted on April 11, 2014 by A&U in LifeGuide, Treatment Horizons

A functional cure candidate modifies genes to create HIV-resistant cells
by Chael Needle

Gary Blick, MD, AAHIVS, Medical & Research Director of CIRCLE CARE Center and Chief Medical Officer of World Health Clinicians, doesn’t throw the word “cure” around lightly.  As an HIV physician for over thirty years, he remembers when researchers were buzzing about a possible HIV vaccine in 1984 (“give it ten years”) and how the horizon of expectations kept being shifted forward (“give it ten more years”) as predicted deadlines would pass without any good news (“we’re not sure when or if”).

Now, building on years of research and the momentum created by the bone-marrow stem-cell transplant that cured the Berlin Patient (Timothy Ray Brown), attention has increasingly focused on the possibility of a functional cure, the ongoing and sustained control of viral load without antiretrovirals. A functional cure would mean that antiretrovirals, which bring with them lifelong benefits as well as lifelong challenges, such as major expenditures (the U.S. government spent $27.7 billion in research, services, and treatment of HIV in 2012 alone), kidney and bone marrow toxicities and other side effects, would no longer be needed long-term. With early but significant successes, a gene-therapy product, pioneered by Sangamo Biosciences called SB-728-T, has found its footing among the nascent field of functional-cure candidates.

Dr. Blick is excited about the results from initial clinical research on SB-728-T, but his excitement is tempered with wait-and-see realism. Sharing the latest news about this new therapy, he had a busy time as a presenter at this year’s Conference on Retroviruses and Opportunistic Infections (CROI 2014). Data from a raft of SB-728-T clinical trials led by Sangamo BioSciences, and in which Dr. Blick is an investigator, shows significant viral load reduction through an intravenous infusion of billions of a patient’s own CD4+ T-helper cells, ones that have been extracted, genetically modified, and re-infused into the body.

What’s extracted? First blood is extracted and then the individual’s own CD4+ T-helper cells are separated out to be modified. CD4+ T-helper cells, much needed for immune protection, are rendered ineffective and die off as a result of HIV infection. SB-728-T infusions have shown long-term increases in CD4+ T-helper cells, which correlates with increased CD4 central memory cells and gene-modified central memory cells.

What’s modified? Using Sangamo’s proprietary genome editing technology—zinc finger nuclease, or ZFN—the extracted cells’ DNA is modified to mimic those one percent of individuals who have been found to be immune (or largely resistant) to HIV because of a natural (and apparently harmless) genetic mutation: CCR5delta32. Having CCR5delta32 results in the expression of a shortened, or truncated, and non-functional CCR5 protein, whose co-receptors are needed for HIV to gain entry into cells. Individuals who have two copies of the mutation are virtually immune, and this is one possible mechanism that has tagged some individuals as elite controllers or long-term non-progressors, meaning some are still able to be infected by HIV but also able to indefinitely control HIV with low or undetectable HIV-1 viremia without antiretrovirals.

What happens after re-infusion? Billions of cells are reintroduced and go through a process of engraftment. Researchers used one cohort to study to what extent, and at what dose, this engraftment is primed by a short-term, one-time infusion of a chemotherapeutic agent known as Cyclophosphamide, or Cytoxan (CTX).

Another cohort showed that CD4 cells can be significantly increased, viral load decreased as much as ninety-nine percent, and the ZFN-modified CD4-cell count can be increased with increasing doses of CTX therapy. Two of three subjects treated with the highest dose of CTX remain on treatment interruption for eleven and twelve weeks with stable or lowered levels of viral load.

Overall, the study showed that an individual’s T cells can be safely engineered via ZFN-based genome editing to make them HIV-resistant and safely infused, resulting in decreases in HIV viral load off antiretroviral therapy.

In another cohort discussed at CROI, one patient has shown ongoing control of viral load with nearly undetectable levels of HIV for thirty-one weeks (now thirty-five weeks as we went to press) without antiretrovirals. This patient, who looks to be on his way to a functional cure, was discovered to have one copy of the CCR5delta32 mutation and has been enrolled in a Phase II trial focused on other individuals without identical pairs of genes for the same trait (heterozygous). “We figured it would be a whole lot easier to do the gene modification if you only have one of two alleles that we needed to modify,” notes Dr. Blick. In other words, this process mimics homozygous individuals, who have two copies of the CCR5delta32 mutation. This patient at baseline had a greater percentage of T cells where both alleles were modified and fully resistant to HIV. Levels of circulating cells with biallelic modification of CCR5 may correlate with control of viral load, according to early analysis. The information will add to the bank of knowledge of how to best use this gene-modified therapy with individuals who do not carry any mutation.

Dr. Blick reports that this individual’s gene-modified T cells are also being analyzed to see if they may be hiding HIV DNA within them.

Currently the gene-modified therapy uses an adenovirus vector as a delivery system. The limitation of the adenovirus vector is that it may cause the body to produce antibodies, which ultimately can interfere with the engraftment of the associated gene-modified cells.

Thus, Sangamo is looking at other delivery systems, namely, mRNA (messenger-RNA). As RNA is a natural part of our bodies, unlike the adenovirus, explains Dr. Blick, the body will not produce any antibodies to run interference against the engraftment of the gene-modified cells and strengthen the possibility of an efficacious functional cure, as well as allow for repeated infusions, if found necessary.

The gene-modified, CCR5-disrupted cells function to not only resist infection by the most common strain of HIV but prevent its persistence.

Significantly, the modified cells have been to shown to have a longer life than the unmodified cells when exposed to HIV during a planned interruption of antiretrovirals, and, importantly, have been found to circulate where latent HIV hides out, such as gut-associated lymphoid tissue. “Lymphocytes have a normal lifespan. And T cells are lymphocytes,” reminds Dr. Blick. “So you know they’re going to have a normal lifespan, typically no greater than 120 days. If infected with HIV and not immune they’re going to die earlier than 120 days. The lifespan of the gene-modified cells—the half-life of gene-modified cells [was shown to be] something like forty-eight weeks, almost one year. We’re actually learning now that it’s going to be quite a bit longer. These gene-modified cells, for some reason, last significantly longer than if they weren’t genetically modified.”

This discovery of preferential survival has been enlightening in terms of measuring the reach of gene-modified cells. “As we’re giving 10 to 40 billion T cells, you expect to see a big bump up in the person’s CD4 cell count and then come down gradually, during treatment interruption, toward the end of treatment interruption, or if they stay on treatment interruption. But they always stayed somewhere around two to three times higher than the individual’s baseline. So, when the cells come down, where are they going?

“We know these T cells are trafficking into lymphoid tissue. These T cells are going into those reservoirs, just like the old T cells did with virus in them.” The difference here is important as antiretroviral drugs have not been shown to follow these infected cells into the reservoirs. “These gene-modified cells will not have virus in them because they’re immune and will fill up these reservoirs. We’ve demonstrated that already.”

Asked if this type of gene-modify therapy might work best in virally suppressed treatment-experienced patients, Dr. Blick responds: “At the very beginning when we started this clinical trial, about a year and a half ago, we thought a T-cell ratio, the CD4/CD8 ratio over 1 would be the parameter that would predict the best responses. We thought that an individual who was HIV-positive for less than ten years would give the best responses. We learned through the clinical trial that was not so. So now we’re treating anybody, no matter what their duration of HIV is or what their CD4/CD8 ratio is.

“But there are some exclusion criteria for these first group of patients. To get into these studies, you have to have 500 or more T cells, and you’ve got to be undetectable, because we don’t want virus replicating at the time you’re giving the gene therapy. In fact, when we give the gene therapy, we wait an additional six weeks for older T cells to die off so that the engraftment of the gene-modified T cells can take hold. And six weeks after we do the gene therapy is when they come off their medication.” As the trials are using a chemotherapeutic agent, the FDA requires other criteria to be met, as well, such as platelet counts of 200,000 and neutrophil counts of 2,500 or greater.

“We’ve been learning as we go along but so far we’ve had nothing negative to say about [the therapy],” notes Dr. Blick. Mild nausea seems to be the most severe occurrence.

Next steps in this research include the addition of a study arm to continue studying CTX dosing to achieve the best engraftment of cells (results presented were based on 1 gram/meter2; the new arm will look at 1.5); finalizing the technology for an mRNA-vector gene modification; and, once all the data from this Phase I/II study is collected about cell infusion and CTX dosing and checks out completely for safety, moving onto a Phase IIa study.

“This is really, really early data at this point,” Dr. Blick reiterates. “So, as long as everything keeps going well with this clinical trial, we have that first sign of a prolonged functional cure [in a person] now at thirty-five weeks; and now we have a second person who dropped about ninety-nine percent of his viral load, 1.9 logs. He’s still doing well. Early numbers, very few people in these Phase I clinical trials—so it’s best to say we’re cautiously optimistic.

“For me, as I’ve been doing research since 1990, understanding and uncovering all of these key findings as we go on is one of the most exciting things about doing this. We always have to give the credit to the patients for even getting involved with us and helping further the whole science of this, but just to watch this process step by step by step and learning how these things work and potentially coming up with the first functional cure for HIV is such an exciting field to be in, and such an exciting time right now.”

◊For more information about World Health Clinicians, log on to: www.worldhealthclinicians.org. For more information about Sangamo BioSciences, Inc., visit: www.sangamo.com.
« Last Edit: April 13, 2014, 03:10:33 PM by freewillie99 »
Beware Romanians bearing strange gifts

Offline YellowFever

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #438 on: May 07, 2014, 09:03:20 AM »
I've recently learned, from watching Behind The Scene videos of Lion King, The Musical, that Rafiki (the baboon that goes naaaaa zewenya mama de chi baba) was modelled after the Sangoma in South Africa. Sangomas are faith healers/shamans/oracles that are prevalent in SA. I wonder if the name Sangamo was a play on that word...Abit off topic from OP but I cant but indulge in abit of brain tickling...
08/2010 HIV- 08/2012 HIV+
10/2012 CD4 415(15%)
04/2013 CD4 457(15%)
10/2013 CD4 520 (20%) VL 650 (wtf?)
02/2014 CD4 410(20%) VL 390 (yay!)
08/2014 CD4 580(?%)

Offline Dr.Strangelove

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #439 on: May 07, 2014, 11:42:52 AM »
From what I understand on their 'About Us' section, the name is derived from Sangamon County, Illinois.

Offline YellowFever

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #440 on: May 07, 2014, 01:33:57 PM »
*bubble bursts*....I didn't manage to read the side bar bit when I looked it up...
08/2010 HIV- 08/2012 HIV+
10/2012 CD4 415(15%)
04/2013 CD4 457(15%)
10/2013 CD4 520 (20%) VL 650 (wtf?)
02/2014 CD4 410(20%) VL 390 (yay!)
08/2014 CD4 580(?%)

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #441 on: May 13, 2014, 12:55:05 PM »
Quick Update:  I went back to Quest for a different study/trial and learned that Sangamo will be using a different vector for its trial this summer.  Many of us were DQ'd from the first trial because of the presence of antibodies to the adenovirus (a cold virus).  So they are using a different vector this time.

Also, they said that certain T-Cells may be better at killing of HIV.  HIV targets them first.  So if you go on meds early, you may have more HIV fighting T-Cells. 

I'm on the list for the next trial.  If I get accepted, I'll provide updates of how it goes.  I think it's supposed to open sometime this summer.

Offline Jmarksto

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #442 on: May 13, 2014, 01:40:35 PM »
Thanks Geobee, I appreciate the updates.
03/15/12 Negative
06/15/12 Positive
07/11/12 CD4 790          VL 4,000
08/06/12 CD4 816/38%   VL 49,300
08/20/12 Started Complera
11/06/12 CD4   819/41% VL 38
02/11/13 CD4   935/41% VL UD
06/06/13 CD4   816/41% VL UD
10/28/13 CD4 1131/45%  VL 25
02/25/14 CD4   792/37%  VL UD
07/09/14 CD4 1004/39%   VL UD

Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #443 on: May 14, 2014, 01:41:54 AM »
The new approach use MRNA for delivery, which also has a higher percentage of modification. It seems they will start a stem cell trial this summer too.

Offline Hoyland

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #444 on: May 26, 2014, 10:17:38 PM »
Looks like Sangamo will receive another $5.6M of public funding from the CIRM to start their next Pl study.

http://www.cirm.ca.gov/sites/default/files/files/agenda/140529_AGENDA_ITEM_8_SP3_May_ICOC%20_0.pdf

Offline Matts

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #445 on: May 28, 2014, 05:18:35 AM »
Is this ZFN research similar to Sangamo?
The Aarhus University has published some papers, but I am not a ZFN expert.


"HIV can cut and paste in the human genome

Aarhus University has developed a technology that uses the HIV virus as a tool in the fight against hereditary diseases - and in the long term, against HIV infection as well. The technology repairs the genome in a new and safer manner..."

http://health.au.dk/en/#news-2163

"Targeted genome editing by lentiviral protein transduction of zinc-finger and TAL-effector nucleases"
http://elifesciences.org/content/3/e01911
tivicay/kivexa

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #446 on: June 10, 2014, 11:21:38 AM »
For you science nerds out there, here's a pretty detailed slide show from a few months back regarding Sangamo's upcoming Hematopoietic stem cell (HSC) trial.  It was presented at the World Stem Cell Summit last December.

http://medical.wesrch.com/paper-details/pdf-ME1XXFH5NBPBK-genome-editing-with-zinc-finger-nucleases#page1
Beware Romanians bearing strange gifts

Online geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #447 on: June 12, 2014, 06:27:07 PM »
So I'm getting screened in 2 weeks at Quest / San Francisco.

In the previous trial, you could only get one injection of the modified T-Cells since it was delivered in the cold virus.  After the first injection, your body developed ABs to the cold virus, so a second injection would be ineffective.

In this new trial, multiple injections are possible.  They don't use a virus.  Apparently they use a laser to poke a hole in the cells so that the ZFN's can get in there.  This seems like total science-fiction and it must be a tiny laser.  But the upshot is since no viral vector is used, you don't get ABs, and you can get multiple injections.

In this trial, people will be receiving up to 3 injections.  You get the injection, go on a STI, see what happens! 

George

Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #448 on: June 24, 2014, 01:33:27 AM »
Best Luck!

Offline Cosmicdancer

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #449 on: June 24, 2014, 12:09:19 PM »
Yes, best of luck.  I'm hoping they enroll you.
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%

 


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