HIV research has reached the point that a cure may be possible. “HIV is a complicated disease, and it’s very encouraging to see advancements,” says Elizabeth Wolffe, Ph.D., Sangamo BioSciences spokesperson. “We’ve seen antiretroviral therapies that have made HIV a chronic disease. Now we’re starting to envision strategies to arm the body’s immune system to fight the virus. The industry is beginning to embrace the idea of cure strategies.”
Frost & Sullivan predicts a compound annual growth rate (CAGR) of 7.5% between 2012 and 2019, with 2012 sales estimated at $5.58 billion for Europe. Globally, BCC Research predicts market growth for HIV therapeutics at 4.6%. It projects global sales of $14.1 billion in 2016. Branded HIV products were expected to account for $13.2 billion of that. Generics, particularly in the developing world, make up the difference and are projected to grow commensurately.
Research got a boost in June when researchers at the NIH discovered how HIV attacks immune cells. Scientists saw that the DNA breaks that occur when HIV integrates its genes into cellular DNA activate DNA-protein kinase, triggering CD4+ T-cell death. This finding suggests that early, even prophylactic, treatment of individuals with drugs that block viral replication may not only prevent viral replication but also improve immune system function.
Sangamo BioSciences is using another approach to improve immune function with the ultimate aim of providing a functional cure. “HIV kills the CD4+ T cells such that the immune system seems never to regain control unless there is a delta 32 mutation in the CCR5 gene (which encodes the major co-receptor for HIV entry into CD4+ cells),” Dr. Wolffe explains.
“If the mutation is in both CCR5 genes, people can be exposed but not infected. If the mutation is in only one of the CCR5 genes, progression slows, giving rise to long-term nonprogressors.” The reason, she says, is that the R5-tropic strain (which is the most common strain at the early stages of infection) needs both CCR5 and CD4 to infect the cells.
Sangamo’s zinc finger protein (ZFP) technology, when attached to a nuclease or DNA-cutting enzyme, creates a new “designer” molecule—ZFN—that enables specific genes to be knocked out or have their expression disrupted. In repairing the break caused by the cutting enzyme, the cells often insert an error that makes the genes nonfunctional.
Sangamo is evaluating ZFP technology in two Phase II studies. Sangamo takes T cells from an HIV-infected individual treated with ART, treats the cells to disrupt the CCR5 gene, and about a month later, infuses the cells (SB-728-T) back into the patient, providing a population of T cells that is resistant to HIV and that also can mount an immune response against HIV and other opportunistic infections.
“We’ve had encouraging results,” Dr. Wolffe says. “The HIV-resistant T cells seem to traffic, moving throughout the body. They have been found in the gut tissues as well as the bloodstream.” Increasing levels of CD4 cells also were found in all patients. “Although the virus returns as patients are taken off ART, viral load decreases have been observed in several patients, with two reaching a transiently undetectable viral load."