Gene therapy promises to be a singular advance in the treatment of both acquired and genetic diseases at the most fundamental levels of pathology. Specifically, the development of gene transfer methods into the heart is attractive given that coronary artery disease is the leading cause of morbidity and mortality in the United States. Despite advances in the prevention and treatment of this disorder there remains a large population of patients who are not optimal candidates for percutaneous or surgical revascularization, usually because of severe distal vessel disease or previous failed revascularization procedures. Coronary collateral development is an important adaptive response of the ischemic heart in this situation, but often the collateral circulation is inadequate and results in severe angina pectoris despite maximal medical therapy. A new strategy to treat these often disabled patients involves the local delivery of vascular cytokines to induce new blood vessel growth (neoangiogenesis) in the ischemic myocardium. It was recognized early on that gene therapy could play a major role in neovascularizarion approaches. Many different gene transfer methods have been tried with varying levels of success in animal models and phase I human clinical trials. Further work is required to develop the methods for expressing angiogenic transgenes in the heart. During Phase I, a minimally-invasive and clinically viable in Vivo delivery system of naked plasmid DNA (pDNA) to the heart will be developed. In Phase II, these studies will be extended by testing the clinical benefits of pDNA delivery of hVEGF expression vectors for treatment of cardiac ischemia in a pig chronic coronary occlusion model (ameroid constrictor). These studies will form the basis for the commercial development of this therapy during Phase III. PROPOSED COMMERCIAL APPLICATIONS: The SBIR proposal will fund pre-clinical studies that will form the basis for human clinical trials and an IND application to the FDA and NIH- RAC. Its commercial development will be accomplished by the initiation of clinical trials (sponsored by Mirus) and its licensing to larger pharmaceutical and biotechnology companies in order to have several clinical studies performed at other medical centers within the next three years.