Atherosclerosis is the major form of coronary heart disease and a primary cause of non-accidental death in America. Multiple risk factors contribute to arteriosclerosis such as: hypertension, elevated total serum cholesterol, low density lipoprotein (LDL) cholesterol, low levels of high density lipoprotein (HDL) cholesterol, diabetes mellitus, occlusive vascular diseases, severe obesity, and cigarette smoking. The progression of vascular atheromatous intimal fatty streaks or plaques appears to be through the intra- and extracellular accumulation of lipid in foam cells from circulating lipoproteins. The composition and levels of serum lipoproteins, molded by genetics and or environmental influences, are complex but appears to have an important role in determining the prediction of artherosclerosis. Recent development and progress in the area of post-natal gene therapy, may provide a means to alter the composition of serum lipoproteins and limit atherogenesis. The primary goals of this proposal is to develop a myogenic expression system for post-natal gene therapy, to deliver increased amounts of lipoprotein lipase in the experimental Watanabe hyperlipidemic rabbit model system and improve its lipid profile and reverse atherogenesis. In developing a strategy, we considered ex vivo approaches utilizing cellular transplantation. Although efficacious in animal studies, ex vivo gene therapy might be problematic and impractical for human application. In vivo DNA-mediated gene therapy, in which DNA vectors are presented directly to the target organs, appears, on the other hand, to be the practical choice for human gene therapy. Muscle tissue has the potential to become a primary target organ for somatic gene therapy. Muscle offers an easily accessible site for the injection of therapeutic genes and most importantly plasmid DNA can be taken up into muscle nuclei as non-integrated extrachromosomal DNA, that results in the expression of that gene for extended periods of time. In order to use muscle as a gene therapy model, it will be necessary to: (1) Develop a potent myogenic vector that elevates the level of gene expression activity several orders of magnitude over standard known vectors, in order to deal with the inefficiency of naked DNA uptake; and (2) improve vector uptake and reduce vector degradation into muscle nuclei. Through a combination of improvements in both muscle vector design and vector delivery vehicles, muscle will be a highly suitable target tissue for expression of therapeutic genes that will help to ameliorate cardiovascular disease states.