The long-range goal of this Program Project is to develop viral vector-based gene transfer strategies for treating genetic aqnd acquired cardiopulmonary disorders. To this end, a group of investigators with diverse, yet complementary, interdisciplinary interests and expertise and expertise has established an integrated research effort that is underscored by a common interest in practical applications of gene therapy. A major focus of the Program is the development of improved methods for gene transfer using recombinant AAV (rAAV) and lentivirus vectors. Project 3 (Muzyczka) will focus on the basic changing viral tropism through the insertion of foreign ligands into the capsid gene. Project 4 (Chang) will investigate ways of improving lentiviral vector yields and study the biodistribution of lentiviruses. Along with the vector development components, there is an emphasis on solving practical issues related to gene therapy for diseases of the heart and muscle. Project 2 (Flotte) focuses on genetic disorders of beta-oxidation of fatty acids within the mitochondria. Disorders of mitochondrial fatty acid oxidation (FAO) as a group represents a relatively common class of metabolic disorders, the most common of which typically present with either Sudden Infant Death Syndrome (SIDS) or with a combined cardiac and skeletal myopathy. The recent development of rAAV vectors for highly efficient transduction of hepatocytes and myofibers present new tools for the study of FAO disorders and project 2 will focus on short-chain acyl CoA dehydrogenase (SCAD) and long chain acyl CoA dehydrogenase (LCAD) defects, whose deficiency results in myopathy. Project 1 (Byrne) will focus on a deficiency in the lysosomal enzyme, acid alpha-glucosidase (GAA). This 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. Project 1 will focus on the development of alternative rAAV serotypes and targeted vectors to improve the efficiency and distribution of gene delivery for this disease. In addition, outcomes of vector distribution and biochemical effect will be tested by new MRI/MRS techniques. To assist the projects, the Program has established a Vector Core Laboratory and a Pathology Core. The Vector Core will supply vectors of uniform and reproducible quality6 to all subprojects, and investigated improved methods of generating rAAV. The Pathology Core (Core C) will carry out biodistribution and toxicology studies for all subprojects. Finally, an Administrative Core (Core A) will insure centralized fiscal management and oversight for the subprojects. The Cores will also serve as a mechanism to insure rapid exchange of information among all subprojects.
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