The overall purpose of this Investigator Award proposal is to consolidate the applicant's career in the field of translational gene therapy research for the treatment of HIV infection. The advent of highly active antiretroviral therapy has been associated with a decline in the incidence of opportunistic infections and prolonged survival. The ability of these drug combinations to greatly suppress virus replication has raised the question as to whether complete eradication of HIV can be achieved in infected patients. Obstacles toward this goal include the presence of an infected quiescent cell pool, the development of drug resistance, drug toxicities, and cumbersome regimens that hinder compliance. The goal of genetic therapies is the replacement of the HIV-1-infected cell reservoir with cells that have been genetically engineered to resist HIV-1 replication. Consistent with the UCLA AIDS Institute's goal of developing innovative therapies for the treatment of AIDS, the applicant has led the effort to develop a gene therapy program within the Institute that has the primary goal of implementing translational studies in this field. This program is driven by basic research discoveries in the area of vectoring and transduction technology, and by in vivo modeling of gene therapy strategies in the SCID-hu mouse model for HIV infection. The applicant has considerable experience in the field of stem cell gene therapy. He has carried out preclinical studies to optimize transduction efficiencies of retroviral vectors into hematopoietic stem cells, has optimized the SCID-hu mouse system to model anti-HIV stem cell gene therapy strategies in vivo, and has applied these results to the design of two stem cell gene therapy studies for the treatment of HIV infection, which are currently ongoing.
The Specific Aims of this proposal are to: 1. Optimize engraftment of stem cells transduced with antiviral genes.
This Aim will focus on modeling strategies to increase the overall HIV cellular target pool that carries antiviral genes. The following trial design will be tested: i) effect of genetic therapy in multi-drug resistant patients; ii) need for myelosuppression prior to transduced stem cell infusion; and iii) safety and transduction efficiencies of HIV vectors as novel delivery systems for stem cell transduction in HIV infection. 2. Optimize the in vivo efficacy of stem cell gene therapy by further characterizing the effects of antiretroviral therapy in thymic reconstitution and by modeling novel genes, and trial designs in the SCID-hu mouse model of thymic development and HIV infection. 3. Determine whether treatment of HIV-infected human subjects with autologous hematopoietic stem cells engineered to carry anti-HIV genes is associated with a degree of immune restoration. Novel markers of immune reconstitution will be studied in patients treated in the various studies outlined in this proposal. Their sensitivities and specificities will be assessed, and their power in predicting immune reconstitution, as assessed by traditional markers, will be measured and correlated with clinical endpoints, including freedom from opportunistic infections and overall survival.
| Amado, Rafael G; Mitsuyasu, Ronald T; Rosenblatt, Joseph D et al. (2004) Anti-human immunodeficiency virus hematopoietic progenitor cell-delivered ribozyme in a phase I study: myeloid and lymphoid reconstitution in human immunodeficiency virus type-1-infected patients. Hum Gene Ther 15:251-62 |
