This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Familial hypercholesterolemia is a heritable disease that is believed to be an excellent candidate for gene therapy. The genetic defect responsible for low density lipoprotein (LDL) receptor deficiency in our pedigreed familial hypercholesterolemic rhesus monkeys has been identified as a nonsense mutation in exon 6 of the LDL receptor gene. This defect in the LDL receptor gene results in the expression of a protein truncated at a position corresponding to amino acid 284 of the human LDL receptor. The defect has segregated with the phenotype of spontaneous hypercholesterolemia through three generations. This is the only primate model of familial hypercholesterolemia (FH), and proof of efficacy and safety of gene therapy in this model would be a major accomplishment toward human gene therapy for this disease. The objective of the program project is to examine the effect of the hepatic transfer of rhesus LDL receptor and VLDL receptor genes to LDL receptor defective rhesus monkeys. The goal is to demonstrate that transgenes reduce plasma LDL levels, slow development of arterial lesions, and are safe during a 24-month period. The helper-derived adenovirus/transgene complex (HD-Ad-LDL-R) provides good expression in mice for more than 6 months and we anticipated similar results in rhesus. Ad-Ad holds great promise for gene therapy since the genes coding for viral proteins, the source of antigenicity, have been removed. Our first attempts to treat rhesus with HD-Ad-LDL-R resulted in good gene expression and reduction in cholesterol levels, but for only 2 weeks; less than 1% contamination of the preparation with helper virus induced an immune response that limited expression. The results of this project will be used to develop procedures for human clinical trials.
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