by Darrin S. Joy and Shawn Le
City of Hope researchers have demonstrated the first successful, long-term persistence of anti-HIV genes in patients with AIDS-related lymphoma treated through gene therapy. The study appeared online June 16 in the journal Science Translational Medicine.
 David DiGiusto works on a potential treatment for AIDS-related lymphoma and HIV. (Photo by Markie Ramirez) |
In the investigational therapy, patients underwent autologous hematopoietic cell transplantation (HCT) in which their own blood stem cells were collected and genetically engineered with three anti-HIV ribonucleic acids (RNAs) that block HIV from infecting new cells.
The gene therapy was developed by City of Hope’s John J. Rossi, Ph.D., Lidow Family Research Chair in the Department of Molecular and Cellular Biology. It uses RNA molecules called ribozymes and other short strands of RNA known as siRNA— short for small interfering RNA — to selectively block specific genes and hinder 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 are effectively resistant to HIV infection. Additionally, the siRNA inactivates the virus directly, and a third component, called a TAR decoy, interferes with a key protein that boosts HIV growth.
The goal of the therapy is to reboot the immune system to identify HIV and mount a response to the infection, lowering the amount of virus in the blood.
“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,” said David DiGiusto, Ph.D., professor in the Department of Hematology & Hematopoietic Cell Transplantation and the paper’s lead author. “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 genes. They then infused the patients with a mixture of modified stem cells and normal stem cells and measured how long the new genes stayed in the patients’ blood samples. None of the patients reported any negative side effects from the gene therapy.
 John Rossi (Photo by Markie Ramirez) |
“We still see evidence that the patients are producing the therapeutic genes, including the siRNA, as long as two years after transplant,” said John Zaia, M.D., Aaron D. and Edith Miller Chair in Gene Therapy and chair of the Department of Virology. Zaia leads the human clinical trial of the therapy and is senior author of the paper.
Autologous HCT is a standard treatment for AIDS-related lymphomas. The procedure aims to replace the diseased bone marrow with healthy, functioning cells. While the procedure may put the lymphoma into remission, the underlying HIV infection still remains. Patients must take antiretroviral therapy for the rest of their lives — and the virus may eventually grow resistant to the drugs.
The gene therapy research eventually may yield a cure for both the cancer and the HIV infection. The team continues research and clinical trials to improve the efficiency of their process, so future patients can receive more genetically modified stem cells and boost their resistance to HIV.
Other City of Hope researchers on the study include Amrita Krishnan, M.D., Lijing Li, Ph.D., Haitang Li, Ph.D., Shirley Li, M.D., Anitha Rao, Ph.D., Shu Mi, M.D., Priscilla Yam, M.S., Sherri Stinson, Ph.D., Joseph Alvarnas, M.D., Simon F. Lacey, Ph.D., Jiing-Kuan Yee, Ph.D., Larry Couture, Ph.D., David Hsu, Ph.D., and Stephen J. Forman, M.D.
