Gene Therapy Promise For Treating AIDS – Replication Stopped by “Monkey Wrench” – Improved Immune Function In Patients With HIV

Gene Therapy Promise For Treating AIDS – Replication Stopped by “Monkey Wrench” – Improved Immune Function In Patients With HIV

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Early tests using Gene therapy provide hope for treating AIDS (Acquired Immune Deficiency Syndrome). We reported that a similar technique was used to treat patients with Melanoma skin cancer in September.

Gene therapy involves removing immune T-cells and in this case genetically modifying them for (Human Immunodeficiency Virus) HIV resistance. Typically, gene therapy involves growing more cells outside the body and then placing them back into the patient.

Instead of chemical or protein based HIV replication blockers, this approach is genetic and uses a disabled AIDS virus to carry an anti-HIV genetic payload. The modified AIDS virus is added to immune cells that have been removed from the patients’ blood by apheresis. The immune cells are then purified, genetically modified, and expanded by a process that the researchers developed. The modified immune cells are then returned to the patients’ body by simple intravenous infusion.

The researchers report in the online edition of the Proceedings of the National Academy of Sciences that “viral loads” of the patients remained stable or decreased during the study. One patient showed a sustained decrease in viral load. T-cell counts remained steady or increased in four patients during the nine-month trial. Additionally, in four patients, immune function specific to HIV improved.

The researchers say that this new lentiviral vector (of which HIV is an example) approach shows promise in patients where other treatments have failed. Doctor Carl June, MD, of the Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine, said “The new vector is a lab-modified HIV that has been disabled to allow it to function as a Trojan horse, carrying a gene that prevents new infectious HIV from being produced. Essentially, the vector puts a wrench in the HIV replication process.”

The gene therapy allows the patients’ own T-cells to inhibit HIV replication via the HIV vector and its anti-viral cargo. The HIV vector delivers an antisense RNA molecule that is the mirror image of an HIV gene called envelope to the T cells. When the modified T cells are given back to the patient, the antisense gene is permanently integrated into the cellular DNA. When the virus starts to replicate inside the host cell, the antisense gene prevents translation of the full-length HIV envelope gene, thereby shutting down HIV replication by preventing it from making essential building blocks for progeny virus.

The patients in this study had an infusion of 10 billion of their own modified T-cells. This works out to about 2 to 10 percent of the number of T-cells in an average person. The T-cell count was unchanged early after the infusions. “We were able to detect the gene-modified cells for months, and in one or two patients, a year or more later,” says Levine. “That’s significant – showing that these cells just don’t die inside the patient. The really interesting part of the study came when we saw a significant decrease in viral load in two patients, and in one patient, a very dramatic decrease.”

The new vector is based on a lentivirus, a subgroup of the well-known retroviruses. The study and its safety profile to date have now opened up the field of lentiviral vectors, which have potential advantages over other viral vectors currently being studied because they infect T cells better than adenoviruses, a commonly used viral vector. Lentiviruses also infect non-dividing or slowly dividing cells, which improves delivery to cells such as neurons or stem cells, thus enabling the evaluation of gene therapy in an even wider array of diseases than before. Furthermore, lentiviral vectors insert into cellular DNA in such a way that may be safer than other gene therapy vectors. This is because lentiviruses appear to insert differently from other retroviruses that have caused side effects in other trials involving stem-cell therapy. In addition, gene insertion by lentiviral vectors is attractive for potential therapeutics since it enables long-term gene expression, unlike other viral vectors where expression is lost over time.

Penn researchers are now recruiting for a second trial using the VRX496 vector with HIV patients whose virus is well controlled by existing anti-retroviral drugs, a group of patients who are generally healthier and have more treatment options available. This trial will use six infusions rather than one and is designed to evaluate the safety of multiple infusions and to test the effect of infusions on the patients’ ability to control HIV after removal of their anti-retroviral drugs. The hope is that this treatment approach may ultimately allow patients to stay off antiretroviral drugs for an extensive period, which are known to have significant toxicity, especially after long-term use.

VRX496 was designed and produced by the Gaithersburg, Md. biotech company VIRxSYS Corp.

By Marsha Quinn
Best Syndication Health Writer



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