Researchers Explore Gene Treatment To Obliterate HIV Before It Does Damage

Thomas Merigan, MD, the George and Lucy Becker Professor of Medicine in infectious diseases at Stanford University School of Medicine, is seeking volunteers for a study to test a possible method of empowering an infected person's own cells to destroy HIV as it enters the cell. The process involves removing the patient's stem cells - the ones in the bloodstream that form the different immune system cell types that HIV infects, such as T cells and macrophages - and inserting a gene that produces an HIV-obliterating enzyme.

"This is a broad-spectrum treatment that could integrate well with other therapies as the disease progresses, as it will in all patients eventually," said Merigan, who is collaborating with other researchers at UCLA and St. Vincent's Hospital in Sydney, Australia, under the sponsorship of Johnson & Johnson Research. "The goal is to genetically engineer the cells and make them resistant to infection."

The strategy developed by Merigan and his colleagues relies on the fact that the genetic information of HIV is encoded in RNA rather than DNA. Enzymes called ribozymes can chew up RNA at very specific sites, rendering it inactive. If a ribozyme specific to HIV RNA were present inside the cells that the virus infects, then it could constitute a first-line defense against the invasion. Even if HIV did make it into the cell and replicated, the ribozyme could potentially cleave the HIV RNA at various steps during the virus' life cycle. With this unique approach to warding off HIV infection, the enzyme produced by a person's own vulnerable cells could demolish the critical genetic instructions of HIV while not affecting his or her RNA.

"With this technique, we'd like to be able to offer an additional approach for patients who in their own minds appear to be doing quite well," said Merigan. "We know there is a sufficient risk that patients will eventually need more than the 19 drugs currently available."

A total of 70 patients will be enrolled at three sites for this stage of the testing. The participants will be randomly assigned to receive either the ribozyme gene therapy or a dummy gene. Johnson & Johnson Research produces the reagents used for introducing ribozyme into the blood stem cells.

In the field of AIDS treatment, there is recognition that an approach like the one Merigan is testing would be a huge development in the ability to combat HIV. David Evans, an information and advocacy associate for Project Inform, a San Francisco-based national nonprofit working to end the AIDS epidemic, said, "Experiments of this type fall perfectly in line with Project Inform's agenda to refocus researchers toward a cure for HIV rather than indefinite treatment with costly antiviral drugs that consistently lead to drug resistance and long-term toxicities."

Martin Delaney, founding director of Project Inform, said he applauds the researchers for their persistence and continued interest in developing new treatments for HIV/AIDS, but added, "It is too early to comment on the potential of this particular experiment and, even if successful, it will be several years before the results can be turned into a widely accessible therapy."

Merigan said that similar studies testing the strategy of using gene therapy in more than 1,200 patients have proven the technique to be safe. The safety studies for the current trial looked at a total of 14 patients and found no safety concerns.

Merigan discussed a scare a few years ago when two babies undergoing gene therapy developed leukemia, which was successfully treated. He noted that the HIV trial had been delayed for two years while the trial's safety design was examined by the National Institutes of Health, the U.S. Food and Drug Administration and local review boards. He said the verdict was that the immune system of adults with HIV differs greatly from that of babies, whose immune systems are not fully formed, and that they should not face the same risk.

The criteria for potential study participants are strict at this stage: men and women with HIV who are between ages 18 and 45, on only the first or second round of anti-retroviral therapy, a relatively low amount of virus in the blood (less than 50 particles per milliliter of blood) and a reasonably high level of T cells (300 cells per microliter of blood or greater). Pregnant women or those with any AIDS-related illnesses will not be included in this trial. Those who are interested should call (650) 723-6231.

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Others in the study team in the division of infectious diseases at Stanford include Andrew Zolopa, MD, associate professor of medicine; Michael Harbour, MD, clinical instructor; Debbie Slamowitz, study coordinator for clinical trials; Jane Norris and Sandy Valle, physician assistants; Patricia Cain and Sylvia Stoudt, staff nurses; and Mark Winters, research assistant.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.