About 20 years ago, scientists found that a few individuals carry a deletion mutation known as CCR5 delta32 are resistant to HIV infection, because HIV needs CCR5 and/or CXCR4 as a co-receptor to enter T cells.
This information led to the development of CCR5 antagonists to inhibit viral entry into T cells. In August 2007, the FDA approved Pfizer’s Selzentry (maraviroc) for the treatment of adults infected with HIV. A diagnostic test is used to confirm if a patient is infected with only CCR5-using HIV (R5).
Unfortunately, maraviroc generated sales of only £96 million in 2012, far short of expected $500 million. The drug’s label includes a black box warning about hepatotoxicity and allergic reaction. It is ineffective in patients infected with CXCR4-using HIV (X4 or mixed). Moreover, the drug costs more than competitive therapies.
While the marketing disaster disappointed investors, scientists were excited with the story of Timothy Ray Brown, the first and only person in the world cured of HIV.
Timothy was an acute myeloid leukemia patient with HIV. His doctors arranged for him to receive a hematopoietic stem cell transplant. But they added a game-changing twist to this standard treatment: they picked a donor with CCR5 delta32 mutation.
Three months after the first stem cell transplant, levels of HIV rapidly plummeted to undetectable levels while his CD4 T cell count increased. Timothy is considered cured. The results were published in the New England Journal of Medicine.
The case of Timothy opens the possibility of curing HIV infection with stem cell. While suitable matched donors with CCR5 delta32 mutation are rare, we can take patient’s blood-forming cells called HSPCs out, edit them, and transplant them back. Both CRISPR/Cas9 and ZFN gene editing technology could precisely knock the CCR5 gene out of HSPCs.
Sangamo Biosciences (NASDAQ: SGMO) is a leading company focused on ZFN technology. The company’s lead candidate, SB-728, is an autologous T-cell product in which the CCR5 gene is disrupted via ZFN technology. The first-in-man study of SB-728 has been published in the New England Journal of Medicine.
Patients received a single infusion of 10 billion autologous T cells, 11-28% of which were CCR5-modified. The CD4 T-cell counts significantly increased from a median of 448/μL at baseline to 1517/μL at week 1. The median concentration of CCR5-modified CD4 T cells at week 1 was 250 cells/μL, accounting for 13.9% of circulating CD4 T cells. The decline in CCR5-modified cells was significantly less than the decline in unmodified cells (-1.25 vs -7.25 cells/day).
Median increase in CD4+ T cell counts was 256 cells/μL at the end of 36 weeks. Is the increase in CD4+ T cell counts clinically meaningful? Hard to say. Actually, SB-728 did not demonstrate sustained and profound viral load suppression. Ultimately, patients had to goes back on the highly active antiretroviral therapy. To date, no patient with HIV has been cured by SB-728.
Sangamo’s approach is obviously far different from the treatment of Timothy. Timothy received stem cells from a donor while Sangamo provides mature T cells. Timothy’s entire immune system was replaced by one from a donor. However, in the trials of Sangamo’s SB-728, patients’ HIV-susceptible immune system remains in place.
Sangamo has an ongoing Phase II trial, SB-728-mR-1401, where patients will receive repeat doses of SB-728 (up to 40 billion) after Cytoxan pretreatment, a common method to enhance engraftment of T-cells. I believe repeat doses of SB-728 will work better than a single infusion. However, it is still difficult to predict whether SB-728 will cure HIV.
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