(Taken from abstract) Recent advances in molecular biology have made possible the use of genes as therapeutic agents for a variety of congenital and acquired diseases including AIDS. Stem cell gene therapy for AIDS offer several potential advantages including protection of the multiple lineage of the hematopoietic cells susceptible to HIV infection as well as long-lived reconstitution. There are considerable barriers to the stable integration and expression of foreign genes in hematopoietic cells in vivo and experiments in non-human primates offer the opportunity to address these issues in an in vivo experimental model. Recent studies from this laboratory have demonstrated that the introduction of either an RNA decoy or SIV specific ribozyme into primitive CD34+ hematopoietic cells can induce a relatively high level of resistance to SIV infection in both T-cells and macrophages derived from these cells. The objective of this proposal then is to examine the ability of hematopoietic stem and progenitor cells transduced with these genes to engraft in normal and SIV infected macaques and to give rise to the hematopoietic cells resistant to SIV infections.
Three specific aims are proposed.
Specific Aim 1 : To optimize engraftment of hematopoietic stem cells transduced with candidate therapeutic genes in normal macaques.
Specific Aim 2 : To examine the ability of RNA decoy and SIV specific ribozyme to protect hematopoietic cells from SIV infection in vivo.
Specific Aim 3 : To examine the ability of genetically-modified hematopoietic stem cells to engraft and differentiate SIV-infected macaques.
