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Zinc Finger-Modified CD4-Cell Booster Transplant Working in Pilot Trial
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51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Transplant of CD4 cells modified in their zinc finger nuclease boosted CD4 counts in 9 people who achieved an undetectable viral load with antiretroviral therapy but had persistently low CD4 counts [1]. The procedure has been safe in the 9 study participants and normalized CD4/CD8 ratios in those with an abnormal ratio when this phase 1 trial began.
The principle behind SB-728-T is simple. This zinc finger DNA-binding protein transcription factor, developed by Sangamo Bioscience, disrupts the gene that makes CCR5 coreceptors sprout from CD4 cells [2,3]. When CD4 cells lack CCR5, HIV has a harder time infecting them. SB-728-T aims to propagate a population of CD4 cells resistant to HIV infection and thus to boost CD4 counts in poor CD4 responders and, perhaps, to make antiretroviral therapy unnecessary.
CD4 cells are collected from study participants and exposed once to SB-728-T, which generates cells lacking the CCR5 coreceptor. The cells are transduced with an adenovirus vector, expanded, then reinfused into the donor. Ideally, this zinc finger-modified population expands further in the body into a durable set of HIV-resistant CD4 cells.
Ronald Mitsuyasu (University of California, Los Angeles) and colleagues from other sites are conducting a phase 1 study that enrolled 9 antiretroviral-treated people with an undetectable viral load but a CD4 count still between 200 and 500. Study participants received 10, 20, or 30 billion modified CD4 cells. Mitsuyasu and coworkers saw study participants weekly for 1 week than monthly for the first 11 months. As in all gene therapy studies, he noted, safety follow-up will continue for 15 years.
The study group had a median age of 53, a median CD4 count of 384, and a median CD4 percent of 27.2%. Study participants had been infected with HIV for a median of 21 years.
At the time of this report, median follow-up duration stood at 337 days. So far there have been no serious adverse events. Of the 60 adverse events recorded, 53 were mild, 6 were moderate, and 1 (low back pain probably not related to the procedure) was severe. Two thirds of these adverse events occurred within 24 hours of the procedure, and all resolved.
Polymerase chain reaction determined that modified CD4 cells made up 0.2% to 2.8% of CD4s in the peripheral circulation at day 28, and those cells have persisted throughout follow-up. CD4 counts in these 9 people rose by a median of 163 cells through day 180. CD8 counts rose by a median of 33 cells over the same period. As a result, CD4/CD8 ratios returned to normal.
Modified CD4 cells could be detected in the rectal mucosa by day 14, a finding indicating that potentially HIV-resistant cells take residence in this critical site. However, the modified cells make up only a small proportion of rectal CD4 cells.
Mitsuyasu and colleagues calculated that the level of modified CD4 cells in their study is about 8-fold higher than in previous CD4-cell adoptive transfer studies. When pressed by attendees to explain this result, Mitsuyasu declined to offer a hypothesis, saying that the researchers are still analyzing data.
The investigators concluded that the modified CD4 cells engraft, expand, and persist for at least 1 year in people with HIV. They proposed that their preliminary data "suggest that SB-728-T offers the potential to reconstitute the immune system in HIV patients."
References
1. Mitsuyasu R, Lalezari J, Deeks S, et al. Adoptive transfer of zinc finger nuclease modified autologous CD4 T-cells to aviremic HIV-infected subjects with suboptimal CD4 counts. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract H1-375.
2. Perez EE, Wang J, Miller JC, et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008;26:808-816.
3. aidsmeds.com. SB-728-T. http://www.aidsmeds.com/archive/SB-728-T_2574.shtml.
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