“Molecular scissors”: Gene therapy locks out HIV, paving the way to control virus without antiretroviral drug

PHILADELPHIA—University of Pennsylvania researchers have successfully genetically engineered the immune cells of 12 HIV positive patients to resist infection, and decreased the viral loads of some patients taken off antiretroviral drug therapy (ADT) entirely—including one patient whose levels became undetectable. The study, appearing today in the New England Journal of Medicine, is the first published report of any gene editing approach in humans.

The phase I study was co-authored by researchers at Penn Medicine, the Albert Einstein College of Medicine and scientists from Sangamo BioSciences, which developed the zinc finger nuclease (ZFN) technology, the T cell therapy approach used in the clinical trial.

This study shows that we can safely and effectively engineer an HIV patient’s own T cells to mimic a naturally occurring resistance to the virus, infuse those engineered cells, have them persist in the body, and potentially keep viral loads at bay without the use of drugs,” said senior author Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine at Penn’s Perelman School of Medicine. “This reinforces our belief that modified T cells are the key that could eliminate the need for lifelong ADT and potentially lead to functionally curative approaches for HIV/AIDS.”

June and his colleagues, including Bruce L. Levine, PhD, the Barbara and Edward Netter Associate Professor in Cancer Gene Therapy in the department of Pathology and Laboratory Medicine and the director of the Clinical Cell and Vaccine Production Facility at Penn, used the ZFN technology to modify the T cells in the patients—a “molecular scissors,” of sorts, to mimic the CCR5-delta-32 mutation. That rare mutation is of interest because it provides a natural resistance to the virus, but in only 1 percent of the general population. By inducing the mutations, the scientists reduced the expression of CCR5 surface proteins. Without those, HIV cannot enter, rendering the patients’ cells resistant to infection.

The study also shows promise in the approach’s ability to suppress the virus. The viral loads (HIV-RNA) dropped in four patients whose treatment was interrupted for 12 weeks. One of those patients’ viral loads dropped below the limit of detection; interestingly, it was later discovered that the patient was found to be heterozygous for the CCR5 delta-32 gene mutation.

Further clinical trials will evaluate greater numbers of modified T cells in a larger cohort of patients, as well as strategies to increase the persistence of more cells in the body to achieve a therapeutic effect.

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