Duchenne's muscular dystrophy (DMD) affects 1 in 3500 live male births. DMD is characterized byprogressive muscle weakness and degeneration often leading to wheelchair dependency in the early teens. Mortality is usually a result of respiratory infection complicated by cardiac failure and most often occurs in late teens or early twenties. It is disappointing that despite tremendous medical advances, the lifespan of the DMD patient has not been significantly improved. There is no known cure and few new successful therapies have been added to the standard treatment repertoire. Overall, the high incidence (1/3500) of DMD, early morbidity and mortality, and lack of effective treatments provide urgent reasons to find other therapies. With the realization that structural defects in DMD will be very difficult to repair given that the defective protein dystrophin is normally part of a large and complex structural network, new thoughts have emerged which focus on muscle regeneration and reduced fibrosis. These 'muscle booster genes'encode for proteins that promote survival and regeneration of the compromised muscles. Myostatin inhibitors in particular have shown great promise and early pre-clinical signs for success. Additionally, adeno-associated virus (AAV)-mediated gene therapy has demonstrated potential for treating a number of genetic disorders. However, without a means of systemic delivery of AAV, the therapeutic effects of gene therapy will never reach cardiac and respiratory muscles needed to avoid problems that are the major causes for mortality in MD patients. Therefore, we propose to determine the optimal delivery method of an AAV vector encoding a secreted myostatin inhibitor by comparing intramuscular versus portal vein delivery in a mouse model of DMD, the dystrophin deficient mdx mouse. By optimizing a delivery method of a secreted myostatin inhibitor either to muscle or liver, we may ultimately gain a systemic therapy suitable for long-term therapy in DMD.
Our Specific Aims are: 1. To determine whether intramuscular or portal vein delivery of AAV1 expressing the secreted myostatin inhibitor, follistatin, enhances muscle strength and coordination in the mdx mouse model of DMD. 2. To determine whether intramuscular or portal vein delivery of AAV1 expressing the secreted myostatin inhibitor, follistatin, can reverse or delay the dystrophic muscle pathology in the mdx mouse.
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