City of Hope leads first successful use of RNA interference to treat HIV infection

Clinical trial of gene therapy for AIDS-related lymphoma shows promising results against both cancer and HIV infection

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DUARTE, Calif.—City of Hope researchers demonstrated what is reportedly the first successful long-term persistence of anti-HIV genes in patients with AIDS-related lymphoma. In the investigational therapy, patients underwent autologous hematopoietic cell transplantation (HCT) in which their own blood stem cells were harvested and genetically engineered with three anti-HIV ribonucleic acids (RNAs) that block HIV from infecting new cells.

The goal of the therapy is "to reboot the immune system" so that the patient's body will once again identify HIV and mount a response to the infection by lowering the viral load.

The gene therapy was developed by City of Hope's Dr. John Rossi, Lidow Family Research Chair and chair and professor, molecular and cellular biology, with technology that uses ribozymes and small interfering RNA (siRNA) to selectively silence specific genes against HIV infection. The ribozyme molecule prevents the patient's white blood cells from producing a protein called CCR5, which HIV needs to enter a cell. The new CCR5-deficient immune cells the patient produces are effectively resistant to HIV infection. Additionally, the siRNA inactivates the virus directly, and a third component, called a TAR decoy sequesters the HIV regulatory Tat protein from the virus.  

"While highly active antiretroviral drugs have managed to turn HIV infection from an immediate death sentence to a long-term manageable chronic condition, we are still seeking a cure," says Dr. David DiGiusto, professor of City of Hope's Department of Hematology & Hematopoietic Cell Transplantation, and lead author of the paper on the therapeutic results, which appeared online June 16 in the journal Science Translational Medicine. "Our research and clinical trials are showing promise for this novel approach to treating HIV patients."

The researchers isolated healthy blood stem cells from four patients and modified the cells to have the therapeutic gene. They then infused the patients with a mixture of modified stem cells and normal stem cells and measured how long the new gene stayed present in the patients' blood samples.  None of the patients reported any negative side effects from the gene therapy, according to the researchers.

"We still see evidence that the patients are producing the therapeutic genes, including the siRNA, as long as two years after transplant," says Dr. John Zaia, Aaron D. and Edith Miller Chair in Gene Therapy and chair of virology, City of Hope, who leads the human clinical trial of the therapy and is senior author of the paper.

A standard treatment for AIDS-related lymphomas is autologous HCT, which replaces the diseased bone marrow with healthy, functioning cells. Although the lymphoma may be put into remission, the underlying HIV infection still remains for HIV-positive patients. Patients are kept on lifelong antiretroviral therapy, but resistance to these drugs often can occur. The gene therapy research may eventually yield a cure for both the cancer and the HIV infection.

The team is continuing its research and clinical trials to improve the efficiency of their process.

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