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Protected T-cells persist and proliferate in HIV gene therapy study
Liz Highleyman, 2014-03-07 12:40:00
Genetically modified CD4 T-cells lacking CCR5 co-receptors reach high levels in the body and are resistant to HIV infection, potentially enabling people to maintain a low viral load while off antiretroviral therapy (ART), according to the latest reports from studies evaluating Sangamo Biosciences' zinc finger technology.
Pre-treating patients with the cancer chemotherapy drug cyclophosphamide (Cytoxan) promotes proliferation and activity of the modified T-cells, and people receiving the highest dose saw the greatest reductions in HIV viral load, according to a presentation yesterday at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) in Boston. A report in this week's New England Journal of Medicine describes outcomes from the first in this series of trials, including one participant with controlled viral load during an extended ART interruption.
Sangamo developed a technique that uses a zinc finger nuclease to disrupt the gene in CD4 T-cells that controls expression of CCR5, the co-receptor that most strains of HIV use to enter cells.
People with two copies of a naturally occurring genetic mutation called CCR5-delta-32 do not produce this co-receptor and are resistant to HIV infection. A man known as the Berlin patient appears to be free of HIV, seven years after receiving transplanted bone marrow stem cells (which give rise to all blood cells) from a donor with this mutation.
In clinical trials of this approach, samples of CD4 T-cells are collected from HIV-positive participants, treated with the zinc finger protein in a laboratory and allowed to multiply. The modified cells, called SB-728-T, are then re-infused back into the same participant. The idea is that these modified cells – being protected against HIV entry – will persist while normal T-cells are killed off by the virus.
This technique has been tested in several cohorts, including people who have not achieved good CD4 cell recovery despite viral suppression on ART, and people who carry a single copy of the natural CCR5-delta-32 mutation, known as heterozygotes.
Researchers have previously reported that the gene therapy procedure is safe and generally well tolerated. The modified SB-728-T cells proliferate and distribute themselves throughout the body like normal T-cells. Study participants experienced substantial CD4 cell gains and decreased virus levels associated with 'bi-allelic' or double-copy gene modification.
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