Myocardial ischemia in patients with coronary heart disease can often be relieved with percutaneous transluminal coronary angioplasty (PTCA). The procedure normally improves circulation to the heart by reducing luminal obstruction. However, the efficacy of PTCA is limited by a high rate of restenosis. Approximately 30-50% of the patients undergoing successful PTCA develop restenosis, usually within a 6-month period. Numerous pharmaceutical therapies have been attempted in man and in animal models, but restenosis remains a major challenge to interventional cardiology. Histological evidence suggests that restenosis is primarily a response of the artery to the injury caused by PTCA. Angioplasty disrupts the intimal layer of endothelial cells as well as the underlying smooth muscle cells of the media. The mechanisms responsible for restenosis are poorly understood, but the common denominator appears to be the proliferation of smooth muscle cells: a process which can hypothetically be altered by genetic transformation. Thus the long-term objective of this pilot project is to determine whether gene therapy, targeted directly to the arterial wall at the site of coronary lesion, can prevent restenosis in a proven animal model system.
The specific aims of this proposal are to: a) Optimize reliable and efficient methods for transferring reporter genes directly into the arterial walls of living swine. In experiments summarized under Preliminary Studies, the P.I. has used replication- deficient adenoviral vectors to efficiently transfer reporter genes directly into the coronary arteries of Hanford miniature swine. The objectives of continuing research are to: i) assess the applicability of recombinant adenoviral vectors for human gene therapy, and ii) determine the optimum catheter design for transferring genes directly into the coronary arteries. b) Construct recombinant adenoviral vectors which will inhibit cellular proliferation and assay their effect upon smooth muscle cells in vitro. The proposed strategy hinges upon the direct transfer of two genes encoding secretory proteins which inhibit smooth muscle cell proliferation: gamma-interferon and somatostatin. It is anticipated that the secretion of these antiproliferative proteins from a modest population of genetically reprogrammed vascular cells at the site of coronary lesion will create a microenvironment inhibitory to restenosis. The anti- proliferative capacities of the adenoviral vectors will first be assessed in primary cultures of porcine smooth muscle cells before proceeding to the in vivo studies. c) Determine the efficacy of the adenoviral vectors in preventing restenosis following PTCA using an established porcine model of atherosclerosis. The P.I. and his colleagues have developed and refined a reliable animal model whose histopathology closely mimics restenosis in man. The pronounced and reproducible coronary restenosis obtained in this model system will serve to test the efficacy of gene therapy in preventing restenosis following PTCA.
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