Heart disease is the leading cause of death in the United States. One million Americans die from heart disease or about one person every 33 seconds. Modification of cardiac muscle performance through gene transfer holds promise as one mechanism to prevent or correct acquired and inherited cardiac diseases. The goal of this proposal is to optimize gene transfer through adenoviral gene delivery in vivo in working myocardium. Adenovirus vectors for expression of important myocardial proteins represent a potentially efficient strategy for correcting deficiencies in the failing heart. In Phase l, we have optimized the conditions for maximal efficiency of gene transfer in vivo in the rat model. In this proposal, we will optimize the conditions for gene transfer and examine closely the expression and inflammatory response induced by adenoviral gene transfer. In addition, we will examine the effect of overexpressing key proteins in murine models of heart failure. A primary concern centers on the stability of gene expression in the myocardium. To date adenovirus reporter gene transfer experiments show that transgene expression can be transient.
There is a rapidly growing market for the ability to test gene therapy vectors. The optimization of a delivery system as well as technology for quantification of clearly defined end-points in well characterized animal models of disease are of high market value to the biotechnology and pharmaceutical industries as well as individual investigators.
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