Cardiomyopathy in infancy is due predominantly to inherited metabolic defects. The molecular pathophysiology of many of these abnormalities is not well understood. Pompe's or infantile acid maltase deficiency is an autosomalrecessive myopathy affecting principally cardiac muscle. This proposal seeks to develop gene transfer strategies for the treatment of this disease, which will also serve as a model systemfor cardiac gene delivery. This disorder is caused by a deficiency in the lysosomal enzyme, acid a-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. Accumulation of glycogen in cardiac and skeletal muscle may impact on muscle function by alterations in myofibrillar ultrastructure including reduction in the myofibrillar content, proteolysis due to abnormal release of lysosomal enzymes or a mass effect of glycogen accumulation. We hypothesize that reconstitution of GAA activity into cardiac muscle cells will ameliorate this disorder by reversal of glycogen accumulation. To test this hypothesis, cardiac gene therapy will used to restore acid-maltase activity in a mouse model of Pompe's disease. Adeno-associated virus will be used to achieve long-term expression of GAA. Gene transfer will be evaluated in a knock-out mouse model of this disease which is a prototypicla storage disease. Detailed physiological assessment oftreated mice will be done by direct measurement of myocardial contractility using pressure-volume determinations. The mechanism of vector persistence following intramuscular delivery will be examine dusing a unique murine model of targeted vector integration and rescue. The long-termg oals of this proposal are to establish the feasibility of gene transfer strategies in the treatment of Pompe's disease and characterize the pathophysiology of this condition. These studies willform the basis for a general approach to the introduction of various recombinant proteins into the hear, leading to the treatment of inherited and acquired forms of heart disease.
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