The urgent need for more effective therapeutic strategies to inhibit replication of the HIV-1 virus and prevent the development of AIDS cannot be overstated. Therapy using currently available antiretroviral agents (nucleoside analogue reverse transcriptase inhibitors --- AZT, ddl, ddC), has proven relatively toxic and of limited efficacy. Gene therapy of HIV- 1 infection, given the irreversible genetic alteration imposed upon the host cells by retroviral infection, appears to offer direct and appropriate treatment of HIV infection, including promise of great potential for long lasting benefits. Preliminary studies performed by investigators involved in each project in this SPIRAT program indicate that hairpin ribozyme inhibition of HIV-1 is an outstanding candidate for aggressive exploration and development as a gene therapy for treatment of HIV-1 infection. The arguments for proceeding to initial human trials at this time are convincing. First, no gene therapeutic agent has been shown to be more potent and persistently active in vitro at this time than the hairpin ribozyme, as expressed by Pol III promoters in retroviral vectors. Second, the gene transfer technology to be used has already been tested and found to be safe in clinical trials, including the same retroviral vector and packaging cell line used in our preliminary studies. Finally, the lack of a reliable and proven animal model for HIV-1 pathogenesis demonstrates the need for human trials in order to secure even a preliminary assessment of efficacy. This project (Project 2 - Clinical Component) is an integral part of a program designed to move these innovative approaches for gene therapy of HIV infection into early phase clinical trials with the greatest possible speed and safety, and to do so in such a manner as to gather the maximum amount of information not only concerning the specific interventional strategies themselves, but also upon the optimal manner in which to design and conduct future studies targeting different cell populations and different patient groups, including plans for expedited execution of expanded clinical trials should initial therapies prove promising. Objectives of this component include: (1) optimization of safety and efficiency of transduction, (2) implementation of the safe administration of ribozyme and control vector transduced cells to infected human volunteers, (3) establishment of the safety of such administration, (4) determination of the best strategies for monitoring the protective effects (if any) of ribozyme expression upon the fate of transduced cells, and (5) accelerated development of additional phase I and phase II protocols for evaluation of ribozyme gene therapy of HIV infection.
Showing the most recent 10 out of 14 publications
