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Ask a Guinea Pig: Gene Therapy Clinical Trials—If and When

, by Matt Sharp

When I first became involved in AIDS treatment activism, many of us felt that the focus of HIV therapy should be the immune system—the target of HIV—rather than the virus. Yet knowledge of the immune system was more limited than it is today, and finding the best place to target our own host defense mechanism was, and still is, a huge challenge.

Today, however, with the understanding that the CCR5 protein on the surface of CD4 cells is an important receptor for HIV to latch onto, scientists have reached the place and time where clinical trials can now be performed with gene therapy technology that can render a person’s own CD4 cells resistant to HIV. This is one way to target our own genetic blueprint with the ultimate goal of stopping AIDS.

People with a unique genetic variation called CCR5-delta-32 lack functional CCR5 on their CD4 cells, rendering them virtually immune to HIV. Piggybacking on this discovery, researchers first developed drug treatments that target the CCR5 coreceptor itself, such as the already approved HIV medication maraviroc (Selzentry) and the experimental drug cenicriviroc. For gene therapy as an HIV cure strategy, proof of concept came when a stem cell transplant from a donor with the CCR5-delta-32 variation cured “Berlin Patient” Timothy Ray Brown of his HIV infection. (Stem cell transplants are also showing positive results in two Boston men diagnosed with HIV and cancer.)

Now there are multiple gene therapy technologies that employ different mechanisms to block the gene for CCR5. The difference between these approaches and CCR5-blocking drugs is that hopefully gene therapy treatment can be given just once or twice, whereas drug treatment equals daily medication for life. The strategy for a “functional cure” is to enable our bodies to keep HIV under control and stop daily antiretroviral therapy—which, although it has been lifesaving for millions of people, can have short- and long-term toxicity issues and is simply not sustainable to universally treat HIV globally.

Furthest along in development is Sangamo Biosciences’ zinc finger nuclease technology (SB-728). I was the second person to enroll in the Phase 1 clinical trial, the first HIV gene therapy trial to show success. After one year, safety was established and improvements in CD4 counts were sustained. (Read a summary of recent SB-728 results here.)

As reported earlier this month at the 16th Annual Meeting of the American Society of Gene and Cell Therapy, genetically modified transitional memory cells—a particular type of CD4 cell—were reconstituted and maintained following infusion into HIV-positive volunteers. This means that this particular gene therapy product may slow HIV disease progression in long-term HIV-positive individuals.

So the question is not if gene therapy for HIV will be safe and effective but when it will become a strategy towards a functional cure.

But the row has to be hoed, so to speak: Some approaches are still in animal studies, and there is a long way to go to prove gene therapy is not only safe and effective in raising CD4 cell counts and suppressing HIV in humans but that this approach can also functionally cure HIV infection. And enrollment in a gene therapy clinical trial likely brings bigger challenges than for drug trials. There may be risks involved in disrupting our own genes, in delivering the gene therapy to its target, and in the blood processing involved. Long-term safety has not been established, and there are considerable unknowns down the road.

That said, unless and until researchers can study gene therapy approaches with actual participants living with HIV, we may never get to a “functional cure” or even improvements upon how HIV is treated today. With HIV gene therapy research ramping up, there will be a need for many people who may be feeling just fine right now to participate in potentially risky studies. So stay tuned, get informed, and get involved!

Resources for the Trial-Curious

Take advantage of these online resources to learn about the potential perks and challenges of joining a clinical trial and to see what studies are enrolling near you.

  • ClinicalTrials.gov: A searchable database of most U.S. clinical trials, with in-depth descriptions of each study.
  • Volunteering in a Clinical Trial: A user-friendly guide to participating in clinical research, from Centerwatch. Read it online or download and print the brochure to take along on your study visits.
  • Guide to Clinical Trials for People with Hepatitis C: It’s not just about hep C! Download this information-packed, reader-friendly guide to learn how clinical trials work and what key questions to ask the research team before joining a trial.
  • HIVresource: This free quarterly newsletter from San Francisco AIDS Foundation links readers with HIV-related clinical trials  in the San Francisco Bay Area.

Selected Sources

June, C. and others. Induction of acquired CCR5 deficiency with zinc finger nuclease-modified autologous CD4 T cells (SB-728-T) correlates with increases in CD4 count and effects on viral load in HIV-infected subjects. 19th Conference on Retroviruses and Opportunistic Infections. Seattle. March 5–8, 2012. Abstract 155.

Lee, G. and others. Long term CD4 reconstitution in HIV subjects receiving ZFN CCR5 modified CD4 T-cells (SB-728-T) may be attributed to the sustained durability of the central memory T-cell subset. 16th Annual Meeting of the American Society of Gene and Cell Therapy. Salt Lake City. May 15–18, 2013. Abstract 58.


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