GENE THERAPY OF CORONARY ARTERY DISEASE

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Gene therapy may represent a novel approach for the treatment of myocardial ischemia. This research project aims at developing adenoviral vectors to transfer the cDNA for endothelial cell growth factors into cardiac cells. The same adenoviral vectors will be used for two different studies: (1) Angiogenesis and improvement of coronary collateral circulation: Neovascularization is expected to improve blood flow to ischemic areas of the myocardium. For this study the adenoviral vectors will be injected into the coronary circulation or directly into the myocardium. (2) Restenosis after angioplasty: Rapid reendothelialization of a segment of coronary artery which has undergone endothelial denudation during angioplasty may be expected to decrease the severity of restenosis and intimal hyperplasia. For this study the adenoviral vectors will be delivered to the localized area of the coronary artery which has undergone balloon dilatation. We have constructed adenoviral vectors which carry the cDNA for the following angiogenic growth factors. (1) Vascular endothelial growth factor (VEGF). (2) Acidic fibroblast growth factor (aFGF). (3) A recombinant form of aFGF which has been modified with the addition of the secretory signal sequence from FGF-4 (sp-aFGF). Unlike the natural form of aFGF this recombinant form of aFGF is secreted into the extracellular space. Our initial studies show all three adenoviral vectors produce a functional protein capable of inducing endothelial cell growth and differentiation in vitro. In additional studies with an adenoviral vector which carries the cDNA for the reporter gene lacZ (AdRSV.lacZ) we have examined whether adenoviral vectors can transduce cardiac cells in the minipigs. We have found that intracoronary injection of Ad RSV.lacZ transduces endothelial cells, vascular smooth muscle cells and myocardial cells. In contrast, intramyocardial injection of AdRSV.lacZ transduces mostly myocardial cells. Studies are now in progress to further characterize the properties of the vectors which carry the cDNA for the angiogenic factors prior to their use in in vivo models of myocardial ischemia and restenosis after angioplasty.