A Biological Therapy Candidate, VRX496, Hopes to Cut Down HIV Replication

by Chael Needle

LifeGuide [Treatment Horizons]

Recently, the biotech VIRxSYS Corporation announced plans to forge ahead with its five-patient lentiviral vector trial. After Phase 1 safety results of the initial three patients dosed with VRX496-modified T cells had been demonstrated, the independent Data Safety Monitoring Board unanimously recommended that the remaining two patients be dosed. The Phase 1 trial—led by the University of Pennsylvania’s Drs. Rob Roy MacGregor and Carl H. June—has enlisted five participants who have all failed two regimens of triple-combination antiretroviral therapy. So far, viral loads have not risen above pre-dosing levels and T-cell counts have remained stable.

Dr. Boro Dropulic, Ph.D., founder and Chief Scientific Officer of VIRxSYS, says this is the first clinical trial to use HIV lentiviral vectors in humans, classifying the potential treatment as biological therapy. Biological therapy, or immunotherapy, seeks to mobilize the body’s own immune system against disease. In this case, VRX496-based therapy seeks to deliver modified genes to immune cells where they are integrated into the cells’ genomes. Immune cells are filtered from a patient’s blood, exposed to low doses of the modified HIV vector, and reintroduced to the patient’s body. One advantage of HIV and other lentiviruses over simple retroviruses is that they can introduce these modified genes into non-dividing cells, which of course make up the majority of human cells.

“The technology turns HIV against itself by developing a non-disease-causing HIV vector that contains a molecular scissor, or antisense, that destroys disease-causing or wild-type HIV in CD4 T cells,” Dr. Dropulic explained. During VIRxSYS’s biological therapy, researchers remove T cells from an HIV-positive patient, which are then treated with the HIV lentiviral vector before being reintroduced to that same patient. “HIV vectors are delivered into CD4 T cells to arm them, waiting for wild-type HIV to infect vector-modified cells in a stealth-like manner. When wild-type HIV infects vector-containing cells, the signals it uses to stimulate its own replication [instead] stimulates replication of the HIV vector. This produces a competition between vector and wild-type HIV, [theoretically] resulting in complete inhibition of wild-type HIV replication.”

 The goal of this therapy in HIV-positive patients, says Dr. Dropulic, is “to protect CD4 T cells from HIV-mediated cell death and decrease the HIV viral load to levels that are not conducive to HIV/AIDS disease.”

Once the trial is completed and safety is established, says Dr. Dropulic, VIRxSYS will move ahead with Phase 11 clinical trials designed to determine the efficacy of different dosing regimens. “We believe that patients who have no treatment options left will benefit from the therapy, but once efficacy is established for this group of patients, there is no reason to believe why it would not work for all patients infected with HIV,” says Dr. Dropulic. “Ultimately we believe that VRX496 therapy will be an alternative to HAART; however, it is also possible that the therapy may be used in conjunction with antiretroviral drugs with the goal to lower the number of drugs that need to be taken to suppress viral loads.”

Though long-term safety issues have yet to be established, the chances of HIV mutating and becoming resistant to this type of therapy are theoretically low and might lead to a way out of the drug-resistance loop so many are caught up in.

Chael Needle wrote about GBV-C/HIV coinfection dynamics in the March issue.

June 2004