Sangamo BioSciences, a Richmond, California–based pharmaceutical company, has developed a "zinc fingers" technology that can home in on the CCR5 section of cellular DNA and artificially create a functional equivalent of the delta-32 mutation. They backed the study announced on Monday, along with the nonprofit California Institute for Regenerative Medicine, which was set up by the state in 2004 via a $3-billion bond issue to promote stem cell research.
This first-of-its-kind study involved six male patients aged 48 to 55 at the University of California in Los Angeles and San Francisco. All of them had been infected with HIV for 20 to 30 years but were on therapy and suppressing HIV below the level of detection. But those decades of infection had taken a toll; their CD4+ T-cell counts were between 200 and 500, less than half what is considered normal.
The study gathered circulating CD4+ T cells from the patient's blood via a process called apheresis. At a central processing facility, the cells were modified with the zinc finger process, then those that were successfully changed to carry the delta-32 mutation were expanded, or grown in very large numbers. Finally, 30 billion of them were infused back into the patient.
The results, which were part of a phase I safety study (rather than phase II efficacy study) were soon apparent. Study leader Jay Lalezari of Quest Clinical Research says there was "a significant engraftment and expansion of the cells, a three-fold increase over what would have been predicted." The total CD4+ T cell count increased by at least 100 in five of the six patients. The changes persisted, with 67 percent of cells showing the modification in the blood three months after treatment.
The researchers took myriad other measures during the study and all seemed to move in a positive direction. Lalezari says it is "probably as good as we could have hoped for in this population."
One subject's experience
Matt Sharp is a veteran HIV treatment activist who was concerned with his low CD4+ T cell count. It meant he had to take various drugs as prophylaxis to prevent the development of opportunistic infections. It also meant having to live with the side effects of those drugs. So, he chose to enroll in the zinc finger study.
He is pleased that his CD4+ T cell count roughly doubled to more than 500 and has remained there so far for six months. It meant he was able to discontinue the prophylaxis drugs.
Scott Hammer, an AIDS researcher at Columbia University's College of Physicians and Surgeons and a vice chair of the retroviral conference where the results were presented Monday, says, "This is early work that takes molecular biology into the clinic…. We shouldn't be raising the flag to say we've solved the problem yet."
Lalezari agreed, emphasizing that this is proof-of-concept study demonstrates that it is technically feasible to do the work, and it is safe. The procedure's real test will come when patients stop their therapies. Will the virus remain suppressed or will they have to go back on a drug regimen?
Another step that may be required for a "cure" is developing a parallel genetic "fix" for CXCR4, another co-receptor HIV sometimes uses to enter cells. And it may be that the modified CD4+ T cells will run their life course and have to be replenished periodically. Perhaps it would make sense to modify stem cells as a more permanent source of protection from HIV infection. That, however, raises another set of issues.
Sharp is wary about stopping his HIV drug regimen. He feels his immune system is fragile and is waiting to see how successful the treatment is for other patients who started the program with a higher CD4+ T cell counts. But he does look forward to the day when future developments might bring a cure and allow him to completely stop his HIV medications.