March 2, 2011
Jay Lalezari, M.D., from the University of California-San Francisco presented first-of-its-kind study data on the use of zinc finger nucleases (ZFNs) to artificially disrupt the CCR5 receptor on the surface of CD4 cells, which HIV uses to infect its human host. The study is an attempt to determine if genetically modifying a patient's own CD4 cells could result in the augmenting of the patient's immune system with lasting, HIV-resistant cells.
Some HIV-infected patients who have an undetectable viral load while taking HIV medications continue to have low CD4+ cell counts. Lalezari et al decided to perform their proof-of-concept study on six of these patients: Each was on HIV antiretrovirals, had an undetectable HIV viral load, had a CD4+ cell count between 200 and 500, and had been HIV infected for more than 20 years. The patients were enrolled in one of two cohorts: in one, 10 billion total cells were modified; in the other, 20 billion. The process involved autologous (i.e., derived from the patient) R5-disrupted T cells that were expanded and modified with ZFNs outside the patients' bodies and then infused into the patients. The patients were followed weekly for one month and then monthly for 11 months post-infusion; blood and rectal mucosa samples were taken.
This novel study construction is the result of a history of groundbreaking findings. CCR5 has long been of interest to HIV researchers because many people who are resistant to HIV infection have a mutation in their CCR5 gene: the delta32 mutation. A minority of people of northern European descent (1% to 2.5%) have this mutation in the CCR5 receptor. After studying these patients, the oral CCR5 inhibitor drug maraviroc (MVC, Selzentry, Celsentri) was developed and ultimately approved in the U.S. in 2007. Fears that blocking the CCR5 receptor would lead to more rapid HIV disease progression or the emergence of other health problems have slowly dissipated since the drug was first given to humans in studies. (That said, there are some known adverse effects of CCR5 receptor blocking, including increased susceptibility to West Nile virus.)
At the same time, some clinicians around the world were also trying to think outside the box on how to block HIV entry into CD4 cells. One such progressive thinker was Gero Hütter, M.D., from the Charité-Universitätsmedizin in Berlin. He had an HIV-infected patient with leukemia; he decided to try to treat both the patient's leukemia and HIV via a stem cell transplant using a donor with the delta32 mutation.
Hütter (and his patient) was lucky to find such a donor. The transplant -- which treats leukemia by essentially rebooting the body's immune system and creating new white blood cells -- also had the benefit of wiping out the HIV infection in the patient. The results of this extraordinary case were presented at CROI 2008 without receiving much excitement from the medical community.
It wasn't until almost two years later -- when it was found that the "Berlin patient" was still free of HIV not only in the blood, but in other compartments as well -- that excitement grew. Now, four years later, the patient remains HIV-free, which suggests he is cured of the disease. This has given companies such as Sangamo even more motivation to pursue a potential functional cure via disruption of the CCR5 receptor.
The data presented by Lalezari about Sangamo's ZFN approach showed several things:
This exciting study opens the door to new possibilities, but many questions remain unanswered:
We should be careful not to overreach with these data. Many people are throwing the "cure" word around when talking about this study, but this is just a very preliminary effort to start answering important questions toward that goal.
At a CROI 2011 press conference, Lalezari and other researchers involved in zinc finger nuclease and HIV gene therapy research discussed their findings and the broader implications of those findings. Click here to read that transcript.
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