We have demonstrated previously the utility of hairpin ribozymes targeting the HIV-1 genome in inhibiting virus replication in a variety of target cells, including primary lymphocytes as well as macrophages derived from transduced CD34+ progenitor cells. In September, 1993, we obtained approval from the NIH Recombinant DNA Advisory Committee (RAC) to conduct The major theme of this SPIRAT application is to develop and clinically evaluate gene therapy against HIV infection. The purpose of this SPIRAT application are two-fold: to seek support for the conduct of a phase 1 trial to evaluate the safety and fate of ribozyme gene altered T-cells from HIV-infected individuals in vivo, and to simultaneously develop preclinical studies that would lead to additional, improved clinical protocols (e.g. targeting CD34+ cells, using alternative vectors such as AAV and HIV and using combinatorial approaches as well as feedback from the clinical trial) that could be developed within the term of the SPIRAT award. A clinical component will initiate a Phase 1 clinical trial to evaluate the safety and effects in HIV-1 infected humans of autologous lymphocytes transduced with a retrovirus vector expressing ribozyme that cleaves HIV-1 RNA and to develop clinical protocols for subsequent trials. Dr. Wong-Staals group will focus on the development and comparisons of Adeno-associated virus vector, murine retrovirus vectors and HIV vectors expressing anti-HIV ribozyme(s) for transduction efficiency and Dr. Anthony Ho will focus on preclinical studies of in vitro enrichment, expansion and transduction of hematopoietic stem cells with anti-HIV gene(s) and development of a Phase 1 trial protocol for stem cell transduction.
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