GENE THERAPY FOR LONG-TERM MYOCARDIAL PROTECTION

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DESCRIPTION (provided by applicant): In this application we propose to develop a preventive gene therapy strategy for myocardium protection from future ischemia/reperfusion injury (I/R) involving a single administration of a therapeutic gene with a vector system capable of efficient and long term myocyte specific and inducible expression of the therapeutic gene. We will employ recombinant adeno-associated viral vectors (rAAV) to achieve long-term and stable expression of transduced genes in the myocardium. We will select cis-acting promoter elements that are capable of conferring inducible and cell-specific gene expression and to use these elements as molecular switches to achieve optimal temporal and spatial control of expression of heme oxygenase-1 (HO-1) as the therapeutic transgene. We have reported that transgenic mice with cardiac-directed overexpression of HO-1 develop resistance to I/R-induced myocardial injury; furthermore, a single intramyocardial delivery of HO-1 gene by rAAV in rats, eight weeks in advance of I/R-induced myocardial injury, resulted in dramatic reduction in myocardial infarction, demonstrating that the combination of rAAV vector and HO-1 gene is an efficacious and feasible therapeutic strategy for myocardial protection. Accordingly, in this proposal we will (1) first document the impact of rAAV-mediated intramyocardial delivery of HO-1 on long-term survival following acute myocardial infarction induced by I/R injury and to determine the duration of expression and sustainability of the therapeutic effect of the transgene; (2) we will develop inducible, hypoxia and reoxygenation-sensitive expression of HO-1 as an endogenously regulated therapeutic approach for myocardial protection; (3) We will establish cardiomyocyte specific transgene expression of HO-1, and finally (4) we will develop a combined approach of cell-specific and inducible expression as an ideal strategy for transgene delivery with maximal tissue specificity and safety.