March 6, 2009
The first randomized, double-blind, placebo-controlled, phase 2 clinical trial study conducted to evaluate the efficacy of gene therapy against HIV has proven to be safe and biological active in affected individuals. The study results, published in the online issue of the journal Nature Medicine also suggests the potential of developing this novel cell-delivered gene transfer technique into a once-only treatment against HIV.
The gene-transfer clinical trial headed by Ronald T Mitsuyasu from the University of California, Los Angeles, involved 74 HIV-1-infected adult patients, of whom, one half received the gene therapy while the other was put on placebo treatment. During the study, the researchers isolated CD34+ stem cells from the patients’ blood samples, which hold the potential to differentiate into various types of leucocytes including CD4+ cells. These hematopoietic progenitor cells were further modifed with placebo or gene coding for tat-vpr–specific anti-HIV ribozyme (OZ1). The enzyme prevents the replication of the HIV virus by excising the tat gene encoded by the viral genome.
The subjects, who received the patient-specific stem cells loaded with OZI did not report any treatment-related adverse effect. The study results did not show significant statistical differences between the viral load of OZI and placebo groups at the primary end point (average at weeks 47 and 48). However, the time-weighted areas under the curve for the time period 40 to 48 and 40 to100 weeks were found to be substantially lesser in the OZ1 group. For the entire follow-up period of 100 weeks, the OZ1 group showed an increase in CD4+ lymphocyte count when compared to the placebo group.
Earlier, Strayer, et al. (Molecular Therapy, 2005) evaluated the current status of the gene therapy strategies employed for the treatment of HIV/AIDS. The review reported some of the barriers that hinder the effective translation of the gene therapy approaches to clinical practices. These included uncertainty regarding the most efficacious cell population to target for gene therapy, the specified target cell diffuseness in the body, and duration of gene delivery, which is not effective or sufficient.
Highly active antiretroviral therapy (HAART), comprising of a cocktail of multiple anti-HIV drugs, is found to be more efficacious in treating HIV/AIDS when compared to mono or duotherapy. Some of the major limitations of HAART therapy identified by Fanning, et al. (The Journal of Gene Medicine, 2003) include HIV mutant strains, strict adherence to long-term therapeutic regimen and severe side effects related to the drug use. The study also suggested the genetic modification of target hematopoietic cells as a potential therapeutic regimen for the treatment of this deadly syndrome, as it may induce the constant intracellular expression of an anti-HIV gene that prevents HIV replication and pathogenesis.
As per the statistics published by the Joint United Nations Program on HIV/AIDS (UNAIDS) and WHO in July 2008, the number of people living with HIV/AIDS globally in 2007 was estimated to be around 33 million. The estimate was found to be far higher when compared to the 8 million reported in 1990.
Further validation of this proof-of-concept study through researches and clinical trials may aid in developing an effective gene therapy-based strategy for HIV/AIDS, thereby avoiding the need for extensive HAART therapy and its associated adverse effects.
References
1. Mitsuyasu RT, Merigan TC, Carr A, et al. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34(+) cells. Nat Med. 2009 Feb 15. [Epub ahead of print].
2. Strayer DS, Akkina R, Bunnell BA, et al. Current status of gene therapy strategies to treat HIV/AIDS. Mol Ther. 2005 Jun;11(6):823-42.
3. Fanning G, Amado R, Symonds G. Gene therapy for HIV/AIDS: the potential for a new therapeutic regimen. J Gene Med. 2003 Aug;5(8):645-53.