Hematopoietic stem cells (HSC) provide an attractive target for gene therapy of AIDS by insertion of genes which may inhibit HIV-1 infection. The major limitation to effective use of hematopoietic stem cells for gene therapy has been the low transduction efficiency of human HSC (<1%) seen in all clinical trials to date. Therefore, the therapeutic benefits of expression of an anti-HIV-1 gene in T cells and monocyte cells produced in patients transplanted with transduced autologous stem cells has not yet been evaluated. In this project, we will perform basic, pre-clinical and clinical studies to evaluate and improve methods for genetically modifying hematopoietic stem cells to confer resistance to HIV-1. Specifically: 1. We will use a series of assays of human hematopoietic stem cells to evaluate the efficiency of improved retroviral and lentiviral vectors (from projects 1, 3, 4 and the BLS-3/GMP Core) in gene transduction of human hematopoietic stem cells for inhibition of HIV-1. Studies from the previous SPIRAT grant have provided the basis for several enhancement in vector design, including the incorporation of lineage specific regulatory elements and improved vector production, including the incorporation of lineage specific regulatory element and improved vector production. In addition, combination genes in single vectors which increase antiviral effects (Project 1) will be incorporated into clinical protocols for Pediatric AIDS. 2. We will perform the necessary pre-clinical studies to allow translation of finding from laboratory studies to future clinical trials. 3. We will perform clinical trials of hematopoietic stem cell gene therapy for children with HIV-1 infection. Study objectives will be to measure safety including monitoring immunologic responses to vector gene products efficacy of transduction and engraftment of stem cells, presence and expression of the RevM10 gene and other combination antiviral genes in T cells and monocytic cells produced in vivo, and potentially improved survival of cells expressing RevM10. These studies will increase basic understanding of the current capabilities and limitations of hematopoietic stem cell gene therapy for the treatment of AIDS in a clinical setting, and develop and test new approaches in collaboration with other projects of this program.
| Curran, Michael A; Ochoa, M Sofia; Molano, R Damaris et al. (2002) Efficient transduction of pancreatic islets by feline immunodeficiency virus vectors1. Transplantation 74:299-306 |
