TARGETED GENE THERAPIES FOR AIDS

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We propose to deliver DNA to normal cells for potential treatment and prevention of AIDS. ph-sensitive liposomes and poly-L-lysine linked with specific ligands such as antibody will be used as target-specific delivery vehicles for the exogenous DNA. Two approaches will be taken. In the first, soluble CD4 gene will be delivered to the vascular endothelial cells. Production and secretion of soluble CD4 by the endothelial cells is expected to block the infectious activity of HIV. We will take advantage of a monoclonal antibody specific for the pulmonary endothelial cells to deliver the soluble CD4 gene in a mouse model. The soluble CD4 gene will be placed under the control of a regulatable promoter such that the production of the soluble CD4 could be controlled by the administration of a simple drug. In the second approach we will deliver the thymidine kinase (TK) gene of the Herpes Simplex Virus (HSV) to CD4+ normal cells. The TK gene will be placed under the control of LTR of HIV-1 such that the gene will be expressed at a significant level only when the cell is infected with HIV. Production of large amounts of HSVTK in the infected cells would then make the cells sensitive to drugs which are specific substrates for HSVTK, such as DHPG and acyclovir. The cellular and viral DNA syntheses of the infected cells would be inhibited by these drugs. This approach is potentially a preventative as well as a therapeutic treatment for AIDS. The virtue of the approach lies in three levels of safety guard of the treatment due to: (a) the specificity of the delivery vehicles, (b) the activation of gene expression by HIV infection, and (c) the opportunity to fine-tune the therapeutic efficacy vs. toxicity by manipulating the drug dose and administration regimen. Thus, the project addresses one of the most crucial aspects of genetic therapy, i.e. safety of the treatment.