One of Sangamo's zinc finger nucleases. Credit: Sangamo

The first clinical trial using zinc-finger nucleases to provide long-term resistance to HIV-1 infection has been given the go-ahead by the US Food and Drug Administration. Sangamo BioSciences of Richmond, California, and its clinical partner, the University of Pennsylvania, have begun enrolling the first 12 people in a phase 1 clinical trial to evaluate SB-728-T, a novel zinc-finger DNA-binding nuclease that permanently disrupts the CCR5 gene on CD4+ T cells (Nat. Biotechnol. 26, 808–816, 2008). CCR5 is the major co-receptor used by HIV-1 to gain entry into T cells. A decade ago, researchers found that a Δ32 deletion in the CCR5 gene confers resistance to HIV-infection in the 1–2% of humans who are homozygous for this mutation. Since then, small-molecule approaches designed to block the CCR5-HIV interaction have been attempted, and New York–based Pfizer's Selzentry (maraviroc), for instance, a CCR5 antagonist, gained approval in August 2007. But while the virus eventually develops resistance to small molecules, Sangamo's strategy aims to disrupt CCR5 viral entry permanently by modifying CD4+ T cells. The company plans to isolate CD4+ cells from a patient's blood, apply the engineered SB-728-T agent to bind the CCR5 gene and excise a portion of it, creating a population of T cells with a disrupted CCR5 receptor, which is then injected back into the person. “This is a very clever approach to treating HIV infection, and I think there's a reasonable expectation that it should work,” says Ramesh Akkina of Colorado State University in Ft. Collins, who has developed a CCR5-suppressing, small-interfering-RNA agent currently in clinical trials. The real question, Akkina adds, is how long the engrafted T cells will survive in the body and how often the therapy will need to be administered. A treated person will still have many infected T cells in circulation but the modified cells are expected to replicate faster. Dale Ando, Sangamo's chief medical officer, notes that one of the major endpoints for the ongoing trial is whether the modified autologous T cells expand preferentially and eventually dominate circulating T-cell populations. “If we see expansion of these T cells, as we did in our preclinical studies, then we would hope that patients would achieve long-term nonprogressive status.” A recent publication (N. Engl. J. Med. 360, 692, 2009), reporting that an HIV-infected patient treated with bone marrow from a CCR5− donor had undetectable viral loads 20 months after transplantation, lends support to the notion that T cells may offer long-term protection against infection.