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Author Topic: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach  (Read 359413 times)

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Offline skycee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #350 on: January 25, 2013, 11:46:53 pm »
Fingers crossed, praying and hoping for the best....
Infected September's 2012
Seroconverted October 2012
Elisa test- indeterminate 20th November. 2012
Rapid test - Negative 23th November 2012
Elisa test - Positive 10th December 2012
CD4 - 546, 12th Dec 2012
CD4 600+, VL 6702 26th March 2013

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #351 on: February 13, 2013, 12:30:55 pm »
So Quest San Francisco called back and I'm getting re-screened for the trial.  Last time I bombed out because my adenovirus antibodies titer was too high. 

Getting tested next Thurs, if I get in (the test takes a while), I'll keep y'all posted.

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #352 on: February 25, 2013, 11:46:15 pm »
So I had the blood draw to test T-Cells and VL.  Have to have good CD4s and UD VL for the trial.  If that comes back with a good result, then they'll test for ABs to the A5 virus and if that goes well, they'll do a tropism test.

It's hard to obtain results with the tropism test b/c, after all, they want UD individuals -- so they have to find a minute amount, multiply it, and then test for tropism.  Also, it takes several weeks for the AB test -- if that one comes back with a low AB titer and it looks like I'm eligible, I guess I'll just try to to have less human interaction until the infusion takes place -- because if get exposed to the cold virus, develop antibodies, then the treatment won't work. 


Offline Mishma

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Zinc Finger Nuclease mutations
« Reply #353 on: February 27, 2013, 12:27:46 pm »
I was just a little worried about "off-target" nuclease activity but not so much on-target mutations. This paper, as the title depicts, talks about the later and how this can affect this treatment modality.

Bottom line: Zinc-Finger Nuclease (and this is really what this tread shoud be called) are being used to cleave DNA at a precise location where either the CCR5 receptor is either rendered inert or in the case of the "stacking" technology, used to insert new genetic material-in addition to knocking out the CCR5 gene. Alas, this form of gene therapy is not error prone. Damn.


http://www.nature.com/nmeth/journal/v10/n3/full/nmeth.2364.html?WT.ec_id=NMETH-201303


TALENs and ZFNs are associated with different mutation signatures


Zinc-finger nucleases (ZFNs) and transcription activator–like effector nucleases (TALENs) are of great interest for genome engineering in higher eukaryotic cells and organisms1, 2, 3, 4, 5. These enzymes contain the same FokI nuclease domain and induce site-specific DNA cleavage; the repair of this broken DNA via error-prone nonhomologous end joining gives rise to small insertions and deletions at the cleavage site, often disrupting genetic information. We have observed that, despite their similarities, ZFNs and TALENs are associated with different mutation patterns. We first compared ZFN and TALEN mutation signatures reported in the literature. We calculated the frequencies of insertions, deletions and complex patterns that include both insertions and deletions at target sites in mammalian cells, mammalian and nonmammalian organisms, and plants. Our analysis included a total of 1,456 mutant sequences at 122 target sites reported in 43 independent studies (Supplementary Table 1).
2016 CD4 25% UD (less than 20). 30+ years positive. Dolutegravir, Acyclovir, Clonazepam, Lisinopril, Quetiapine, Sumatriptan/Naproxen, Restasis, Latanoprost, Asprin, Levothyroxine, Restasis, Triamcinolone.

Offline Cosmicdancer

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #354 on: March 06, 2013, 05:21:38 pm »
Here's a summary of Sangamo's presentation today at CROI about its ZFN clinical trials.  The Phase 1 trial is showing sustained reconstitution of the immune systems of participants. 

http://www.heraldonline.com/2013/03/06/4671886/sangamo-presents-new-clinical.html

Data Demonstrate that SB-728-T Possesses Necessary Immunologic Properties to Support a 'Functional Cure' for HIV/AIDS
By Sangamo BioSciences, Inc.

RICHMOND, CALIF., MARCH 6, 2013 — /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced new data from its program to develop a 'functional cure' for  HIV/AIDS  in two presentations at the 20th Conference on Retroviruses and Opportunistic Infections (CROI), held in Atlanta from March 3 to 6, 2013.

The first presentation described data from the SB-728-T Phase 1 study (SB-728-902, Cohorts 1-3) demonstrating that SB-728-T treatment of HIV-infected subjects leads to durable reconstitution of the immune system driven by increases in total CD4+ central memory T-cells (TCM) and CCR5-protected TCM. TCM are long-lived, self-renewing cells that have the ability to remember and react against foreign antigens including HIV.  The data also showed that certain cell surface marker and gene expression profiles may predict which patients will likely respond best to SB-728-T treatment.

"These important data extend our understanding of why SB-728-T treatment improves the immune system as well as the conditions required for optimal engraftment of ZFN-modified T-cells," said Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "They confirm that SB-728-T meets the key immunologic requirements for immune reconstitution in HIV-infected individuals. In addition, analysis of cell surface marker and gene expression profiles of immune system cells in subjects who show superior responses to treatment in terms of increased T-cell counts provides us with important indicators that will aid us in the optimization of our clinical trials."

"The ability of SB-728-T to durably reconstitute the immune system in HIV-infected subjects after a single treatment has never been observed before with any other therapeutic approach," commented Rafick-Pierre Sekaly, Ph.D., Co-Director & Chief Scientific Officer, The Vaccine & Gene Therapy Institute of Florida (VGTI Florida), whose laboratory carried out the analysis. "Improvement in the overall health of the immune system of HIV-infected individuals, as demonstrated by treatment with SB-728-T, is a key step along the path to developing an immunologic approach to controlling and potentially eliminating the virus. We have analyzed the cells that constitute this unprecedented elevation of total CD4+ cell counts, extending our previous observations that the increase is primarily due to durable expansion of the central memory T-cells. Importantly, the level of ZFN-dependent CCR5 gene disruption is sustained in these cells, which is critical for the durable success of this approach."

HIV destroys the immune system by killing CD4+ T cells. The current standard of care for HIV/AIDS is daily treatment with antiretroviral therapy (ART), which suppresses viral load in the blood of most subjects but does not eliminate the reservoir of HIV-infected cells.  In addition, a significant proportion of treated HIV-infected individuals do not experience a restoration of CD4+ T-cell counts to normal levels.  SB-728-T treatment, by eliminating the co-receptor, CCR5, which is necessary for HIV entry to CD4+ cells, is designed to provide a CCR5-negative population of CD4+ T-cells that cannot be infected by HIV but are able to fight opportunistic infections and enable the immune system to control and eliminate the virus. Sangamo's clinical studies have demonstrated successful ZFN-dependent CCR5 gene modification of T-cell populations, including critical cell types such as the TCM.  Studies to date have demonstrated that engraftment of SB-728-T is safe, the modified cells are durable and demonstrate prolonged trafficking and dynamic immunological responsiveness in the gut mucosa, an important HIV reservoir.  The data presented today demonstrate that SB-728-T treatment leads to unprecedented durable increases in total CD4+ T cells that are correlated with increases in TCM and ZFN-mediated CCR5-modified TCM.

"These exciting data support our development program for SB-728-T as a potential functional cure for HIV/AIDS," stated Edward Lanphier, Sangamo's president and CEO. "We have ongoing Phase 2 clinical trials designed to build on our early studies in which we observed a significant correlation between the number of infused CD4+ T cells in which both copies of the CCR5 gene are modified, so-called biallelic modification, and reduction in viral load during a treatment interruption.  We intend to present data from these trials this year."

The first of these ongoing trials (SB-728-902 Cohort 5) evaluates the approximate doubling of bi-allelic engraftment that can be achieved in individuals that have a natural mutation of one of their CCR5 gene copies, CCR5 delta-32 heterozygotes, and seeks to confirm an observation of the occurrence of aviremia during ART treatment interruption (TI).  The second trial (SB-728-1101) examines the ability of a lymphopenic preconditioning regimen to enhance bi-allelic engraftment and reduce viral load during a TI in subjects in which CCR5 is not mutated.

Sangamo expects to present preliminary data in the first half of 2013 and the full data set from both trials by the end of 2013.

Data Summary
Abstract #126 "The Central Memory T-cell is the Critical Component for Sustained CD4+ Reconstitution in HIV Subjects Receiving ZFN CCR5 Modified CD4+ T-cells (SB-728-T)"Wednesday, March 6, 2013 HIV-infected subjects were enrolled in a Phase 1 clinical trial (SB-728-902, Cohorts 1-3) and received a single dose of SB-728-T (5 to 30 billion cells). All subjects were on ART and had stably controlled undetectable levels of HIV in their blood.

The study evaluated safety and tolerability, changes in CD4+ T-cell counts and the ratio of CD4+ to CD8+ T-cells, as well as persistence of SB-728-T in the blood and trafficking of these ZFN-modified cells into gut-associated lymph tissue.
Analysis of data from subjects in the study presented today demonstrated:
·   Treatment of HIV subjects with SB-728-T leads to both acute and long term increases in total CD4+ T-cell counts.
·   Observed level of CD4+ T-cell reconstitution is significantly greater than in previously published T-cell infusion studies without CCR5 modification.
·   Long term increases in total CD4+ T-cell counts correlate with increased TCM and increased ZFN-mediated CCR5 disrupted TCM.
·   Levels of CCR5 disrupted TCM were stable or increased over time compared to other T-cell sub-populations.
·   In addition, analysis of immune cells of treated individuals provided a specific cell-surface marker profile and "gene expression signature" that characterized individuals who showed superior responses to treatment in terms of increased CD4+ T-cell counts.

In the same oral session, data were also presented from a research stage study conducted in collaboration with scientists in the laboratory of Dr. James A. Hoxie, Professor of Medicine at the University of Pennsylvania and Director of the Penn Center for AIDS Research.

Abstract #129 "T-Cells Edited to Express CCR5 or CXCR4 Fused to the C34 Peptide from gp41 Heptad Repeat-2 Exhibit Robust Protection from Diverse HIV-1 Isolates"   Wednesday, March 6, 2013      The data demonstrate potent inhibition of HIV infection in cells expressing a chimeric protein comprising a portion of the HIV envelope fused to either the CXCR4 or CCR5 HIV co-receptors.  Scientists fused the C34 peptide from the gp41 portion of the HIV envelope to the amino terminus of either the CXCR4 (C34-X4) or CCR5 (C34-R5) proteins. Importantly, both C34-X4 and C34-R5 demonstrated potent inhibition of infection by either an X4-tropic or R5-tropic HIV-1 isolate in primary CD4+ T cells, the natural target of HIV.

Webcasts of all the presentations at CROI 2013 can be accessed via the following link:http://webcasts.retroconference.org/m/2013
About SB-728-T SB-728-T is an autologous CD4+ T-cell product in which the gene for CCR5, a co-receptor for HIV entry, is modified via ZFN-mediated genome editing to disrupt the CCR5 protein.  T-cells with a disrupted CCR5 protein are resistant to infection by the most common strain of HIV.

About Sangamo Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic® for the treatment of HIV/AIDS. Sangamo's other therapeutic programs are focused on monogenic diseases, including hemophilia, Huntington's disease and  hemoglobinopathies such as beta-thalassemia and sickle cell anemia. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs).  Engineering of ZFPs that recognize a specific DNA sequence enables the creation of sequence-specific ZFP Nucleases (ZFNs) for gene modification and ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function. Sangamo has entered into a strategic collaboration with Shire AG to develop therapeutics for hemophilia, Huntington's disease and other monogenic diseases and has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the company's website at www.sangamo.com. ZFP Therapeutic® is a registered trademark of Sangamo BioSciences, Inc.

This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references relating to research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform for the treatment of HIV/AIDS, including a potential functional cure of HIV/AIDS, the expansion of clinical studies of SB-728-T in HIV-infected individuals, expected timing for the presentation of clinical trial data and the initiation of additional preclinical and clinical studies of ZFN-gene modification. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo's SEC filings, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo BioSciences, Inc. assumes no obligation to update the forward-looking information contained in this press release.

Read more here: http://www.heraldonline.com/2013/03/06/4671886/sangamo-presents-new-clinical.html#storylink=cpy
Summer, 2007 - &$#@?
November, 2007 - Tested poz, 300,000 vl, 560 cd4
Feb, 2008 - 57,000 vl, 520 cd4, started Atripla
2/2008 - 5/2015 - undetectable on Atripla
May, 2015 - UD, switched to Complera
September, 2015 - UD, 980 cd4, switched to Stribild (Complera interacted with acid reflux medication)
January, 2016 - Stribild, UD, 950 cd4
June, 2016 - UD, 929 cd4

Offline Jmarksto

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #355 on: March 06, 2013, 10:45:11 pm »
Here's a summary of Sangamo's presentation today at CROI about its ZFN clinical trials.  The Phase 1 trial is showing sustained reconstitution of the immune systems of participants. 

http://www.heraldonline.com/2013/03/06/4671886/sangamo-presents-new-clinical.html

I don't see any mention of effect on viral load from the SB trials in this news release.  The Street.Com also blasts the company (see the link below) implying that they are hyping the technology to keep the stock price up. I have to imagine that if Sangamo had good data on viral load to share they would - the fact that they don't (have the data, or aren't willing to publish it) does not bode well for this technology or the stock price (even after a 7% drop today).

http://www.thestreet.com/story/11861867/1/sangamos-hiv-gene-therapy-is-a-valuation-prop-nothing-more.html

« Last Edit: March 06, 2013, 10:47:20 pm by Jmarksto »
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
11/03/14 CD4   711/34% VL UD
03/13/15 CD4   833/36% VL UD
04/??/15 Truvada & Tivicay
06/01/15 CD4 1100/50% VL UD
10/16/15 CD4   826/43% VL UD
??/??/2017 Descov & Tivicay
2017 VL UD, CD4 stable around 850
2018 VL UD, CD4 stable around 850

Offline Cosmicdancer

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #356 on: March 07, 2013, 01:55:31 am »
But the update at CROI was about the phase 1 trial, in which people were put back on meds after a brief treatment interruption, so everyone is presumably undetectable thanks to the meds.  Thus, there is no viral load data to report.  The phase 2 trial data will be presented later this year, and that will involve indefinite treatment interruptions. 

I think this update about phase 1 is extremely exciting, and very good news for Sangamo since potentially people whose CD4's have not rebounded that well despite being on meds may be able to restore their CD4's with one round of ZFN treatment. 
Summer, 2007 - &$#@?
November, 2007 - Tested poz, 300,000 vl, 560 cd4
Feb, 2008 - 57,000 vl, 520 cd4, started Atripla
2/2008 - 5/2015 - undetectable on Atripla
May, 2015 - UD, switched to Complera
September, 2015 - UD, 980 cd4, switched to Stribild (Complera interacted with acid reflux medication)
January, 2016 - Stribild, UD, 950 cd4
June, 2016 - UD, 929 cd4

Offline Markmt

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #357 on: March 07, 2013, 06:59:17 am »
I agree with cosmicdancer here!....and for some reason the article on street.com makes taking pills for hiv a piece of cake.

"in HIV patients can take a single pill each morning and basically never have to worry about their disease getting worse. These patients will grow old and die of something else before they succumb to AIDS. That's an amazing achievement in a disease that was a certain death sentence 30 years ago."

http://www.thestreet.com/story/11861867/1/sangamos-hiv-gene-therapy-is-a-valuation-prop-nothing-more.html

I think we all know the realities to this.
"Live to love and love to live."

Leo Buscaglia

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #358 on: March 07, 2013, 12:13:59 pm »
I was disappointed that we didn't get an announcement re: VL at CROI but, on the other hand, I still remain hopeful (but less so).  Still, it's been a slow process to recruit for the Cytoxan/SGMO trial, as I've experienced myself. 

First I was bounced for high bilirubin (crazy, since, hello, I'm on Reyataz!).
... then I was bounced for the high A5 antibody (hello, people get colds!).  Then I was bounced because my CD4/CD8 ratio wasn't good enough (close, tho).

Finally, it's been difficult to do a tropism test since they only want UD participants, and it's hard to determine tropism on something that is undetectable.

So all the screening factors mean a lot of delays.  And then there's the whole "do you take the plunge" question.  If you (or I) actually pass the screening, do you go ahead with it?  Watch your VL go up and hope it comes down by the treatment?  That's a little nervous-making.

Having said that I think about other potential cures (Bryologs, therapeutic vaccines, abzymes, treatment intensification, hairpin RNA)  and still think Sangamo (T-Cells or Stem Cells) has the best shot at curing this thing.

They've promised preliminary results on the PII data by the first half of the year.  I can wait a few more months.  And really, what choice do we have?



Offline bhanu_1002

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Offline Matts

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #360 on: March 13, 2013, 04:02:57 pm »
I think that the Sangamo shares a a risky investment at the moment; I would wait for more information about the trials.

Dr. Gero Hütter, made a short presentation about his Berlin-patient,CCR5 and the Sangamo and Calimmune trials. He works for Calimmune now, so I don't know how realistic his assumptions are:

http://www.isheid.com/presentations/mercredi/16-00/hutter/hutter.pdf
Dovato

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #361 on: March 13, 2013, 04:12:50 pm »
Any comments on the below link

http://seekingalpha.com/article/1269121-sangamo-bioscience-the-impending-failure-in-hiv

Sure.  It's written by a guy with a Poly Sci degree who discloses he's short the stock (i.e. betting on it to go down).  He makes several glaring errors / assertions regarding dropping vl loads during treatment interruptions.  That alone marks him as an ill informed hack and not worth listening to.  Regardless, the proof will be in the pudding come May when they present interim Phase 2 results.  Until then, talk is cheap.
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Offline Ann

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #362 on: March 14, 2013, 07:54:25 am »
Any comments on the below link

http://seekingalpha.com/article/1269121-sangamo-bioscience-the-impending-failure-in-hiv


He makes several glaring errors / assertions regarding dropping vl loads during treatment interruptions.  That alone marks him as an ill informed hack and not worth listening to. 


Unfortunately, what FreeWilly just said there can be broadly applied to most/many hacks... er.... "journalists" ~coughcough~ who write news articles and/or press releases on anything to do with hiv/aids, both in the lamemainstream press and for online news outlets.

****

After writing the above paragraph, I went into a general discussion aimed at people who are new to reading information regarding hiv/aids on the internet. I soon realised it was a major derailment of the original intent of this thread, so I decided to take what I wrote and start a new thread with it.

My main dilemma was where to put the new thread; here or in the I Just Tested Poz forum, but I settled on starting it here, mainly because that's where a lot of our newbies with a thirst for knowledge seem to end up. I hope folks read it (and comment) and I hope it helps some people learn to more safely navigate the world of hiv/aids information vs crap (or just terribly reported) science.

Ann
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Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #363 on: May 15, 2013, 04:48:24 pm »
RICHMOND, Calif., May 15, 2013 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today the presentation of new clinical data from its program to develop a ZFP Therapeutic® for HIV/AIDS.  The data, which demonstrate that SB-728-T treatment results in a reduction in the HIV reservoir in HIV-infected subjects, are being presented at the 16th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT).  The meeting is being held in Salt Lake City from May 15-18, 2013

HIV-infected subjects enrolled in Sangamo's ongoing SB-728-902 clinical trial (Cohorts 1-3) received a single infusion of SB-728-T which resulted in a durable increase in total CD4 T-cells driven by increased ZFN-modified CD4 central memory T-cells.  The extent of exposure of subjects to circulating zinc finger nuclease (ZFN) CCR5 protected CD4 T cells correlated with a long term decrease in the peripheral blood mononuclear cell (PBMC) HIV reservoir as measured by proviral DNA.  In addition, two of four evaluable subjects in Cohort 5 of this study showed a decrease of greater than one log in their viral load during a sixteen week treatment interruption (TI) with one of the subjects achieving a transiently undetectable viral load during the TI period. In subjects in which viral load decreased, a measureable anti-HIV response was observed, specifically a multi-functional response of CD8 T-cells to elements of HIV core proteins.
"These data are quite remarkable," commented Dale Ando , M.D., Sangamo's vice president of therapeutic development and chief medical officer. "In previous clinical studies, a decline in the HIV reservoir has never been observed in subjects on long-term anti-retroviral therapy (ART) and any increase in the levels of CD4 cells in HIV-infected subjects is often associated with a concomitant increase in the size of the reservoir.  In contrast, a single SB-728-T treatment of subjects on long-term ART produced a significant and durable improvement in CD4 count and, in the majority of subjects, a notable decrease in the HIV reservoir over time.  An observed correlation with circulating ZFN CCR5 protected CD4 cells is extremely promising."

http://www.prnewswire.com/news-releases/sangamo-biosciences-presents-clinical-data-demonstrating-hiv-reservoir-reduction-in-hiv-infected-subjects-treated-with-zfp-therapeutic-sb-728-t-207530041.html

Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #364 on: May 15, 2013, 05:02:21 pm »
during a sixteen week treatment interruption (TI) with one of the subjects achieving a transiently undetectable viral load during the TI period.

Excellent news, just what I was hoping to hear.    Should we assume the person above went back on ART instead of seeing what happens longer term?

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #365 on: May 15, 2013, 05:35:08 pm »
I actually did'nt expect Sangamo to do this well; but we will have to wait til the end of the year for more info--at the conference on HIV revervoirs in Miami??)

The reservoir info was good news I think.

Calimune's technology is way more sophisticated than Sangamos, So I'm thinking their's will bring better news.  ;)




Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #366 on: May 15, 2013, 05:40:11 pm »
I actually did'nt expect Sangamo to do this well; but we will have to wait til the end of the year for more info--at the conference on HIV revervoirs in Miami??)

The reservoir info was good news I think.

Calimune's technology is way more sophisticated than Sangamos, So I'm thinking their's will bring better news.  ;)

I'm right there with you.   I know long time members on here have "cure" news fatigue (I don't blame them), but both studies open up a whole new level of possibilities. 

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #367 on: May 15, 2013, 08:19:00 pm »
I pondered "transiently undetectable" several times today.  I guess it means they went undetectable and then it came back?

I sort of thought something like this would happen.  Medicine is replete with non-black-and-white outcomes.  Try.  Learn.  Modify. Try again!

So...thinking about it for a bit... I am only transiently disappointed :).  The results were good just after one infusion -- repeated infusions would be a great next step.



Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #368 on: May 15, 2013, 08:26:33 pm »
I pondered "transiently undetectable" several times today.  I guess it means they went undetectable and then it came back?

I sort of thought something like this would happen.  Medicine is replete with non-black-and-white outcomes.  Try.  Learn.  Modify. Try again!

So...thinking about it for a bit... I am only transiently disappointed :).  The results were good just after one infusion -- repeated infusions would be a great next step.

I agree "Transiently undetectable" is new to me as well. 
(interesting HIV-Language Evolving stuff)

Offline buginme2

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #369 on: May 15, 2013, 09:17:14 pm »
Transient = Not Permanent

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Offline JazJon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #370 on: May 15, 2013, 09:24:06 pm »
Transient = Not Permanent

Adjective
Lasting only for a short time; impermanent.
Noun
A person who is staying or working in a place for only a short time.
Synonyms
transitory - passing - fleeting - temporary - momentary

Offline Common_ground

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #371 on: May 16, 2013, 08:20:48 am »
Ill interpret it as they use the word transient because the subject went back on ART, and the TI was scheduled for only 16 weeks, no?

So to say "permanently undetectable" , well then he had to stay of ART forever.

Just like with the Berlin Patient, some claim he shouldnt be declared cured because the virus might bounce back, even its what 6 years ago?
Transient cured maybe? lol
2011 May - Neg.
2012 June CD4:205, 16% VL:2676 Start Truvada/Stocrin
2012 July  CD4:234, 18% VL:88
2012 Sep  CD4:238, 17% VL:UD
2013 Feb  CD4:257, 24% VL:UD -viramune/truvada
2013 May CD4:276, 26% VL:UD

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Offline Ann

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #372 on: May 16, 2013, 08:43:12 am »
Ill interpret it as they use the word transient because the subject went back on ART, and the TI was scheduled for only 16 weeks, no?


It sounds to me like he went back on ART because he experienced viral rebound. Why would he go back on meds if he had an undetectable VL? I sure wouldn't.

"Viral rebound" is what they call it when you have an undetectable *hcv viral load during - and after - hcv treatment, but the VL becomes detectable again in the weeks/months following cessation of treatment. I'm assuming the same terminology would apply here. I would think "transiently undetectable" is more or less a synonym for "experienced viral rebound". Just an edjamakated guess. ;)

It may be that some of these possible hiv cures might be similar to hcv cures in that not all patients will obtain a "sustained response" - ie a cure. Something to keep in mind, folks.

*hcv = hepatitis C, for the uninitiated. 
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Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #373 on: May 16, 2013, 11:10:31 am »
That patient's viral load reached undetectable and then rebounded to low thousands, and stayed off HAART till now.

http://www.investorvillage.com/smbd.asp?mb=1933&mn=53903&pt=msg&mid=12796562

Ill interpret it as they use the word transient because the subject went back on ART, and the TI was scheduled for only 16 weeks, no?

So to say "permanently undetectable" , well then he had to stay of ART forever.

Just like with the Berlin Patient, some claim he shouldnt be declared cured because the virus might bounce back, even its what 6 years ago?
Transient cured maybe? lol



Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #376 on: May 16, 2013, 12:02:23 pm »
I'd grade the results a B with positive (pun intended) upside potential for a better grade when the full results are posted Q4. 

It seems there's a correlation of number of infused modified cells with efficacy which makes the patients treated later in the trial potentially quite interesting.
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Offline buginme2

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #377 on: May 16, 2013, 12:24:07 pm »
Ill interpret it as they use the word transient because the subject went back on ART, and the TI was scheduled for only 16 weeks, no?


No.

I'd grade the results a B with positive (pun intended) upside potential for a better grade when the full results are posted Q4. 

It didn't work and your giving them a "B"?  Your an easy grader.  On what earth do you give someone a B who failed to do what they intended?

The fact that  some patients experienced a durable increase in cd4 cells is something to celebrate.  There are too many people who never experience a rebound of cd4 cells upon initiation of HAART.  That is something to post about.  However, trying to read success on viral load reduction where there wasn't much if any success seems nearsighted.

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Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #378 on: May 16, 2013, 12:41:19 pm »
No.

It didn't work and your giving them a "B"?  Your an easy grader.  On what earth do you give someone a B who failed to do what they intended?

The fact that  some patients experienced a durable increase in cd4 cells is something to celebrate.  There are too many people who never experience a rebound of cd4 cells upon initiation of HAART.  That is something to post about.  However, trying to read success on viral load reduction where there wasn't much if any success seems nearsighted.

Strongly disagree. The data shows that modified CD4 cells have antiviral effect and are able to bring the viral load to undetectable in some patients! Remember, no single HIV drug(not cocktail) can bring your viral load down to that level.

Also, this is very early in Phase 2 trial, it seems, if we have over 10% modified CD4 cells, the results will probably look quite good!!

In the end, for those patients who stayed on HAART. A single infusion leads to durable CD4 increase and even a reduction in viral reservoir in PBMC.  HAART simply can't do it! 

Offline Dr.Strangelove

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #379 on: May 16, 2013, 01:40:45 pm »
I agree with Bug

The CD4 part is great news but the viral load reduction is disappointing.
Only a single person went UD. It seems half of the 'evaluable subjects' didn't show any significant decrease in viral load.

Question: I'm starting to lose track with all those studies. Is this the studies where all of the test subjects have a mutation in one of their CCR5 genes? In that case the reduction in viral load with this therapy would probably even less in people where both CCR5 genes are intact.

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #380 on: May 16, 2013, 02:42:32 pm »
I'd like to see the results in a clincal trial were multiple infusions were given WITHOUT a vector...read a few months ago on here that scientist "poured" zinc fingers onto stem cells-- no vector used-and the % of cells modified was a lot higher compared to  adenoviral vector modified stem cells.

The head of VGTI Florida (Selazy?) seems happy with the results in terms of the reservoirs... ???

And I'd like to see gene therapy + therapeutic vaccines + the strongest anti-reservoir drugs in a clinical trial.  Just saying.  :)

Offline bmancanfly

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #381 on: May 16, 2013, 02:51:55 pm »
I agree with Bug

The CD4 part is great news but the viral load reduction is disappointing.
Only a single person went UD. It seems half of the 'evaluable subjects' didn't show any significant decrease in viral load.

Question: I'm starting to lose track with all those studies. Is this the studies where all of the test subjects have a mutation in one of their CCR5 genes? In that case the reduction in viral load with this therapy would probably even less in people where both CCR5 genes are intact.

Yes the test subjects who saw the viral load reduction had the gene mutation,  which makes these already underwhelming results that much more underwhelming.

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Offline Matts

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #382 on: May 16, 2013, 03:29:30 pm »
Ok it was a failure. I don't know much much cash Sangamo has and if they can conduct further trials or will become bankrupt.
I only see a future if they concentrate on the latent cells, at least they reached a reduction of 70%- better than every HAART. I'm curious what they will do in the next years.
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Offline Miss Philicia

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #383 on: May 16, 2013, 03:35:58 pm »
Can someone summarize? Did this five year old thread go up in flames?
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Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #384 on: May 16, 2013, 04:12:32 pm »
This is NOT a failue per se. Some participants had some positive results with just ONE infusion & with very few cells actually being modified...if I remember correctly, Sangamo's technology has only modified something like 5-6% CD4s in the past  (perhaps antibodies againts the freaking adenovirus is to blame) ...I'd like to see modification in the 30-50% range. Never had my money on Sangamo's technology, but lets just wait till the end of the year for the final results; if Sangamo can demonstrate a clear connection between % of cells modified and VL/CD4s then thats great news in a Proof-of-concept kind of way that more sophisticated technology can do the trick...technology that I believe we might have already, but we just have to wait 3-5 years to start seeing phase 1 trials.  :)

Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #385 on: May 16, 2013, 06:09:31 pm »
The correlation is very strong.
http://www.investorvillage.com/smbd.asp?mb=1933&mn=53925&pt=msg&mid=12797002

The treatment threshold seems to be around 10%.
It would be cool if they could modify over 10% stem cell  :)

This is NOT a failue per se. Some participants had some positive results with just ONE infusion & with very few cells actually being modified...if I remember correctly, Sangamo's technology has only modified something like 5-6% CD4s in the past  (perhaps antibodies againts the freaking adenovirus is to blame) ...I'd like to see modification in the 30-50% range. Never had my money on Sangamo's technology, but lets just wait till the end of the year for the final results; if Sangamo can demonstrate a clear connection between % of cells modified and VL/CD4s then thats great news in a Proof-of-concept kind of way that more sophisticated technology can do the trick...technology that I believe we might have already, but we just have to wait 3-5 years to start seeing phase 1 trials.  :)

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #386 on: May 16, 2013, 07:11:47 pm »
No.

It didn't work and your giving them a "B"?  Your an easy grader.  On what earth do you give someone a B who failed to do what they intended?

The fact that  some patients experienced a durable increase in cd4 cells is something to celebrate.  There are too many people who never experience a rebound of cd4 cells upon initiation of HAART.  That is something to post about.  However, trying to read success on viral load reduction where there wasn't much if any success seems nearsighted.

What can I say?  I'm easy.


Can someone summarize? Did this five year old thread go up in flames?

No, not just yet.  Hold off on that snarkstorm for a few more months until their full Phase 2 trial results come out.
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Offline xman

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #387 on: May 17, 2013, 12:34:19 pm »
why you call it a failure. the studies demonstrated a reservoir reduction and some degree of vl reduction. i guess it's matter of how much cells are infused. if the modified cells exceeds 70% from the total amount the effect would be enormeous. most likely not all the cells needs to be modified to control hiv without haart.

Offline Skydrake

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #388 on: May 19, 2013, 03:50:02 am »

why you call it a failure. the studies demonstrated a reservoir reduction and some degree of vl reduction. i guess it's matter of how much cells are infused. if the modified cells exceeds 70% from the total amount the effect would be enormeous. most likely not all the cells needs to be modified to control hiv without haart.

Because for a patient with a VL reduction (the no. 5-04 below), we obtain three patients with a switch from R5 quasi-species to R5/X4 quasi-species (no. 5-01, 5-02 and 5-05):



The copresence of CD4 CCR5+ and CD4 CCR5- seems the ideal habitat to trigger the switching.

It's a complete faliture, unless Sangamo will demostrate that these three patients have been harbouring dual tropic strains even before the beginning of the trial.
« Last Edit: May 19, 2013, 03:55:30 am by Skydrake »

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #389 on: May 19, 2013, 06:08:16 am »
Sky, don't understand your point here. What switching?

The Berlin patient was R5/4X.

Offline Skydrake

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #390 on: May 19, 2013, 08:13:09 am »
Sky, don't understand your point here. What switching?

The Berlin patient was R5/4X.

But:
1) Patients of last Sangamo  trial could not. From the data released I only see that three patients are R5/4X now, and I don't understand when they become just so that. This is a key point.

2) The Berlin patient treatment isn't a good comparison with Sangamo treatment. He recevied two chemiotherapies and two bone marrow transplants. At least last chemiotheraphy destroyed most previous immune system AND THE GRAFT REACTION DESTROYED LAST RESERVOIRS. It's a common reaction of the new immune cells, from the donor, to take place in the host and destroy previous immune cells, even taking anti-graft drugs. Not only. He recevied ART even during the first period after the transplant.

Instead in the Sangamo treatment there is no graft reaction band does nothing against X4 quasi-species, so ist's very important at least to shorten the period of coexistence of CD4 CCR5+ and CD4 CCR5-.
« Last Edit: May 19, 2013, 08:30:21 am by Skydrake »

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #391 on: May 19, 2013, 11:21:08 am »
I sort of get what you mean now....sort of.

But the Berlin Patient was cured of HIV before he was cured of his leukemia. His second transplant was due to the fact that his cancer sprung back; he did'nt have any rebound by the time he underwent his second transplant...and too think of it, in his case---Only case thus far really--it was easier for the drugs/the host vs graft phenomenon to kill off ALL the virus, then to kill off ALL the cancer stem cells...

About these subjects in the trial, maybe they were R5/4X before the trial, perhaps. Maybe the modified cells killed of enough R5 virus so that the R5/4X was able to get going. Perhaps. Lets just wait for clarification.

I think Sangamo has a gene therapy zinc finger to take care of 4X. But then again, don't think Sangamo can deliver the goods they way we all want. At least not by itself, at least not with one infusion. Personally, I would'nt care of having to go and get 20 infusions over a period of a year or so if it would work...but thats me.

Other Newer gene therapy technologies in pre-clinical (not talking about Sangamo,nor Calimmune) have in mind the R5/4X equation too....the one I am talking about was posted on the forum a few months ago, and their technologies seem light-years ahead of what Sangamo has. Don't worry, we will get there. Patients. :)

Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #392 on: May 19, 2013, 01:50:24 pm »
It is very likely before the infusion. Why?
For HIV to mutate from R5 to X4, you have to throw very strong selection pressure on it (when no or few CCR5+ CD4 left). Sangamo's method only modifies a very small portion of CD4 cell. If the virus is original R5 tropic, there is no real pressure for it to mutate to X4.

Perhaps early in the trial, they were not able to identify they are dual tropic?

Because for a patient with a VL reduction (the no. 5-04 below), we obtain three patients with a switch from R5 quasi-species to R5/X4 quasi-species (no. 5-01, 5-02 and 5-05):



The copresence of CD4 CCR5+ and CD4 CCR5- seems the ideal habitat to trigger the switching.

It's a complete faliture, unless Sangamo will demostrate that these three patients have been harbouring dual tropic strains even before the beginning of the trial.
« Last Edit: May 19, 2013, 02:04:18 pm by greenbean »

Offline Skydrake

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #393 on: May 19, 2013, 02:21:59 pm »
It is very likely before the infusion. Why?
For HIV to mutate from R5 to X4, you have to throw very strong selection pressure on it (when no or few CCR5+ CD4 left). Sangamo's method only modifies a very small portion of CD4 cell. If the virus is original R5 tropic, there is no real pressure for it to mutate to X4.

That small portion of CD4 cells, the CCR5 receptor, is the main door to the lymphocytes, the CXCR4 si only a small back door. If you close the main door, you'll have a very strong pressure for it to mutate to X4 and use the back door.

About how quick HIV is able to mutate, even without a "pressure", read this:

It is estimated that up to 5 mutations may arise with each replication cycle. The daily production of more than a billion new virions in a typical chronically infected patient implies that the virus undergoes 10–100 million rounds of replication daily, resulting in the rapid generation of viral progeny carrying every possible mutation throughout

Source:
http://cid.oxfordjournals.org/content/56/11/1667.full
« Last Edit: May 19, 2013, 02:26:23 pm by Skydrake »

Offline greenbean

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #394 on: May 19, 2013, 04:50:14 pm »
but only a small fraction of whole CD4 cell population has that door closed, while the majority are still CCR5 positive(HIV can use those that are CCR5 positive). So there is no pressure to guide mutation to use CXCR4 (The berline patient case has really big selection pressure, but it didn't happen...). But it might happen once more are more CD4 cells become CCR5 negative.

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

at 1:57:07, a girl asked similar questions, but Carl June didn't think that would happen given the small number of cells modified.

Paula Cannon's explanations regarding the same issue:
http://www.youtube.com/watch?v=IRlvOW0rBkk
at 9:40

Also, there is a price paid for every mutation happened. the majority of mutated virus are not replication competent.

That small portion of CD4 cells, the CCR5 receptor, is the main door to the lymphocytes, the CXCR4 si only a small back door. If you close the main door, you'll have a very strong pressure for it to mutate to X4 and use the back door.

About how quick HIV is able to mutate, even without a "pressure", read this:

It is estimated that up to 5 mutations may arise with each replication cycle. The daily production of more than a billion new virions in a typical chronically infected patient implies that the virus undergoes 10–100 million rounds of replication daily, resulting in the rapid generation of viral progeny carrying every possible mutation throughout

Source:
http://cid.oxfordjournals.org/content/56/11/1667.full
« Last Edit: May 19, 2013, 04:58:28 pm by greenbean »

Offline oh-no

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #395 on: July 04, 2013, 09:02:30 pm »
There was another similar study with HIV immune stem cells from Canada.
The method was called OZ1.

http://www.catie.ca/en/treatmentupdate/treatmentupdate-172/anti-hiv-agents/clinical-trial-gene-therapy-hiv

The scientists took cells from patients made the cells resistant to HIV and infused them back.

Results:
Four weeks after infusion, technicians detected HIV-resistant cells from blood cells in 94% of people in the OZ1 group. One year after the infusion, this figure fell to 12% and two years after the infusion it fell to 7%.
No statistical significance of viral load or cell count.

Stem cells suppose to reproduce themself and produce HIV resistant T-cells.

But the majority (90%) of stem cells sits in the marrow bone. So the marrow bone is the main producer of blood cells and lymphocytes. That is why blood infusion cant repeat the marrow bone transplantation experience of Berlin patient.

In addition to marrow bone transplantation Berlin patient is on the immune suppress medication which suppress HIV. It is more dangerous than arvt. He also developed graft-versus-host disease very strong immune reaction when donor cells attack patient's HIV infected cells.

I'm sure scientists and direction from Sangamo have basic knowledge of human immunity system, they also know about similar OZ1 trials which did not succeed. So they can predict results.

Of course this doesn't mean they should stop experiment. It is a step forward for the science and medicine. With new knowledge some day the new approach will be discovered. But not in the foreseeable future, even for those who is not infected with HIV.
That is why they do their trials so slowly. Time and loud promises brings money for them.
« Last Edit: July 04, 2013, 09:15:11 pm by oh-no »

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #396 on: July 04, 2013, 09:30:31 pm »
Oh no: this is the reference to what you wrote: http://www.catie.ca/en/treatmentupdate/treatmentupdate-172/anti-hiv-agents/clinical-trial-gene-therapy-hiv

Sangamo is light years ahead of OZ1. Calimmune is even way more avanced then Sangamo. City of Hope should have something soon way more avanced then Calimmune...see a pattern? :)

Cheers


Offline oh-no

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #397 on: July 04, 2013, 10:20:36 pm »
All studies just use different methods to make cells resistant to HIV.
This goal is already archived. But this doesn't brings right result for the human body: persistent presence of modified cells, significant VL decline and cell count rise.

Canadian scientists point on future goals.
Gene therapy experiments need to find ways to do the following:
get more CD34+ stem cells to take hold in the bone marrow
prolong the life of CD4+ cells containing gene therapy
demonstrate significant anti-HIV activity (lower VL)

Stem cells multiplies and live longer in bone marrow.
So the goal is to deliver them here. Theoretically it could be the process similar to transplantation, but with autologous cells. In this case there is no need to destroy patient's own immune system with chemotherapy. First bone marrow is took from the bone than modified and than injected back. But today nobody even talk about this.

They move with little steps, when the whole picture is already visible. It is like to produce phone first with 500MB memory than 1GB than 2GB when technically it is already possible to produce phone with 2GB.


However I agree there is always should be a place for the hope.

Offline Hoyland

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #398 on: July 05, 2013, 03:56:58 am »
Quote
All studies just use different methods to make cells resistant to HIV.
This goal is already archived. But this doesn't brings right result for the human body: persistent presence of modified cells, significant VL decline and cell count rise.

Actually the fact that different methods are used means that different outcomes can be achieved. The study referred to used RNA ribozyme to treat the stem cells. Many scientist in the field no longer believe that using a ribozyme on its own can provide the long term benefits required to produce a HIV cure. Both the Calimmune and the CoH techniques involve turning off a gene that produces the CCR5 receptor, which is essential to the entry of HIV into human cells. (CoH additionally use a ribozyme as part of their treatment.) They do this through modifying cell DNA, which means that the modification is replicated each time the cell divides. The potential is for such treatments to last a lifetime, not only halting a current infections (the virus has nowhere to go)  but also preventing future infections. 

There is still a problem of transfection (as was shown in the first CoH trial) but slowly the rate of transfection has been improving. The UC Davis team achieved twice the transfection rate in mice than the original CoH pre-clinical work. The CoH are now working on improving transfection and will conduct a Pll trail when they have completed their current investigations.

Hopefully, it won't be too long before we see some data on transfection rates from the current Calimmune trial. If enough cells can be modified, there is no reason to doubt that those treated will, at some point in the future, produce enough modified cells to rid the body of the virus.

Note: One of the patients in the CoH trail in 2010 is still producing increasing levels of the therapeutic cell even though the original transfection rate was very low. See video.  http://www.youtube.com/watch?v=9XqJyYrYgwU

Offline Hoyland

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #399 on: July 05, 2013, 04:11:30 am »
Sorry, I forgot to mention that Geoff Symonds, one of the co-authors of the paper, worked for J&J at the time the referenced paper was produced and he is now Calimmune's Chief Scientific Officer.

 


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