The long-range goal of this Program Project is to develop viral vector-based gene transfer strategies for treating genetic and acquired cardiopulmonary disorders. To this end, a group of investigators with diverse, yet complementary, interdisciplinary interests and expertise has established an integrated research effort that is underscored by a common interest in practical applications of gene therapy using recombinant AAV [rAAV). A major focus of the Program is the development of improved methods for gene transfer using recombinant AAV (rAAV) vectors. Project 1 (Muzyczka) will focus on the basic biology of AAV viral entry and intracellular trafficking. Physical, biochemical and genetic approaches will be used to identify sites on the capsid involved in co-receptor attachment, the capsid structural changes that occur during cell entry and the cellular proteins that interact with the capsid. This will complement work proposed in Projects 2 and 3 which will focus on specific pulmonary and cardiac applications and Core B (Zolotukhin), which will develop capsid libraries that will be screened for heart and lung tropism. Along with the vector development components, there is a major emphasis on solving practical issues related to gene therapy for diseases of the heart and muscle. Project 2 (Flotte) focuses on genetic disorders of fatty acid oxidation (FAO) whose deficiency results in cardiac and skeletal myopathy. This project has made progress in correction of these defects in animal models and will focus on preclinical experiments for the correction of VLCAD and MCAD as well as preclinical toxicology studies of muscle delivery for these defects using AAV8 and AAV9 vectors. Project 3 (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, heart failure within the first year of life. Project 3 will focus on the development of the AAV9 serotype which has been successful in correcting the cardiac deficiency. Experiments will address the mechanism of AAV9 persistence, the mechanism of transduction in relation to cardiac and neuronal cells, and rAAV2/9-mediated transduction and toxicology in non-human primates. To assist the projects, the Program has established a Vector Core Laboratory (Core B, Zolotukhin), a Pathology Core (Core C, Campbell-Thompson) and an Imaging Core (Core D, Walters). The Vector Core will supply vectors of uniform and reproducible quality to all subprojects, and investigate the use of capsid libraries to develop new viral tropisms. The Pathology Core (Core C) will carry out biodistribution and toxicology studies for all subprojects. The Imaging Core will provide MRI/MRS and optical imaging support for in vivo experiments. 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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Skarlatos, Sonia
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University of Florida
Schools of Medicine
United States
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Smith, Barbara K; Martin, A Daniel; Lawson, Lee Ann et al. (2017) Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity. Exp Neurol 287:216-224
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