CORRECTION OF INHERITED CARDIOMYOPATHY USING AAV VECTORS

University Of Florida, Gainesville FL

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Abstract

We have focused in the initial award of this program grant on a model of inherited cardiomyopathy with the goal of establishing and characterizing the model as well as evaluating local vector delivery for correction of the genetic defect. We have successfully generated a model of Pompe disease or infantile acid maltase deficiency, which is an autosomal recessive cardiac and skeletal myopathy which results in hypertrophic cardiomyopathy. The disorder is caused by a deficiency in the mysosomal enzyme, acid alpha-glucosidase (GAA). Enzyme deficiency leads to glycogen accumulation in lysosomes of striated muscle, and in the infantile form, affected infants die of heart failure within the first year of life. This disease like many forms of cardiomyopathy would benefit from global delivery of the corrective gene to myocardium. To continue the progress made in the initial period of the program, we propose to develop gene transfer strategies to myocardium which would be effective for Pompe disease as well as other conditions where global gene delivery are required. The initial strategies used adeno-associated virus serotype 2 for muscle transduction. Recent work on alternative vector capsids and capsid mutants suggest that other serotypes of selective targeting of capsids to a given tissue will improve the efficiency and distribution of gene delivery. We hypothesize that increase efficiency of vector delivery can be accomplished by use of alternative AAV serotypes and specific targeting to cardiac muscle. To test this hypothesis, we will utilize the Pompe disease model to evaluate the delivery of GAA by vectors with AAV serotypes 1, 2, and 5 as well as hybrid having properties of each know serotype. Additionally, we will screen cardiac tissue and coronary microvascular endothelium for novel specific ligand by phage display. Known ligands from cardiotrophic adeno and coxsackie virus as well as novel ligands derived from phage display will be incorporated into capsid mutants developed in Subproject 3. Outcomes of vector distribution and biochemical effect will be test4ed by new MRI/MRS techniques. Additionally, we propose to test the physical delivery methods which will result in efficient and clinically relevant gene transfer to cardiac muscle.