The first phase 2 gene therapy trial for treating HIV has shown some promising results, although it is too early to say if this kind of treatment will be viable, there is enough evidence to justify further research into how to improve the approach, said the investigators.

The research was the work of Dr Ronald T Mitsuyasu of the University of California Los Angeles (UCLA) and colleagues from UCLA and other research centres in the US, Australia and Germany, and was published online in Nature Medicine on 15 February.

Mitsuyasu is the Director of the Center for Clinical AIDS Research and Education at UCLA (CARE), a Professor of Medicine in Residence at the UCLA David Geffen School of Medicine, and an Associate Director of the UCLA AIDS Institute.

Although this first randomized, double-blind, placebo-controlled phase 2 trial in 74 HIV infected adults did not show a statistically significant difference in viral load between the treatment and the placebo groups at the primary endpoint, other analyses “did reveal that the gene therapy seemed to have a modest, but statistically significant, effect at reducing viral load in the treated subjects versus the placebo arm”, said the article summary, which also suggested that the trial provided useful clues about what to improve for the future.

Although highly active antiretroviral therapy (HAART) has greatly improved quality of life and extended the lives of people with HIV, there is a risk of adverse side effects and the virus is starting to mutate into forms that are less responsive, so the need for a new kind of treatment is increasing every day.

Gene therapy has the potential to be a once only treatment that reduces the amount of HIV present in the body, preserves the immune system and avoids having to be on HAART for life.

For the study, Mitsuyasu and colleagues took blood stem cells (CD34+ hematopoietic progenitor cells) from the patients in the treatment group, modified them to carry an enzyme called OZ1, and then reinjected them back into the patients. OZ1 targets two proteins that stop HIV replicating itself. The patients in the placebo group underwent the same procedure except that they received a placebo.

The trial was double blinded, so neither the patients nor the health care team treating them knew whether their stem cells carried the active enzyme or a placebo.

After 48 weeks the results showed there was no statistically significant difference between the two groups in terms of the viral load (the amount of HIV circulating in their bloodstream).

But after 100 weeks, the patients who had received OZ1 had higher levels of CD4+ cells circulating in their bloodstream: CD4+ cells are key immune cells that are targeted and destroyed by HIV.

The authors concluded that:

“This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.”

According to BBC News, Mitsuyasu told the press this was the first study to undergo the tight protocols of a controlled clinical trial where patients didn’t know if they were in the treatment or the placebo group.

Mitsuyasu said that while the treatment is a long way from being ready for clinical use compared to the well tested HAART, the study showed it has potential: they now have “proof of concept” that inserting a single anti-HV gene into patients’ blood stem cells can reduce the virus’ ability to self-replicate.

“Gene therapy has the potential of needing only a one-time or infrequent administration of product and would allow the patients to control their own HIV internally without the need for continuous drug therapy,” he said.

But Mitsuyasu said more trials and long-term follow up were needed to make sure the therapy was effective and safe in the longer term.

“Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells.”
Ronald T Mitsuyasu, Thomas C Merigan, Andrew Carr, Jerome A Zack, Mark A Winters, Cassy Workman, Mark Bloch, Jacob Lalezari, Stephen Becker, Lorna Thornton, Bisher Akil, Homayoon Khanlou, Robert Finlayson, Robert McFarlane, Don E Smith, Roger Garsia, David Ma, Matthew Law, John M Murray, Christof von Kalle, Julie A Ely, Sharon M Patino, Alison E Knop, Philip Wong, Alison V Todd, Margaret Haughton, Caroline Fuery, Janet L Macpherson, Geoff P Symonds, Louise A Evans, Susan M Pond & David A Cooper.
Nature Medicine Published online: 15 February 2009.

Click here for Abstract.

Sources: Journal abstract, BBC News.

Written by: Catharine Paddock, PhD