Pompe disease (1:40000 live births, glycogen storage disease type II, acid maltase deficiency;MIM 232300) is characterized by severe cardiomyopathy and respiratory muscle weakness that affects individuals at an early age. These effects are mediated by a single defective gene encoding the enzyme acid a-glucosidase (GAA), resulting in glycogen accumulation within muscle tissue. Glycogen deposits disrupt the architecture and function of both cardiac and skeletal muscle and cause a debilitating and often fatal condition. Presently, there is no effective cure for Pompe disease and treatment options are severely limited. Enzyme replacement therapy (ERT), the only approved treatment for Pompe disease, must be administered frequently and only provides partial benefit to the patient. Therefore, the focus of our laboratory is to develop a novel therapeutic approach to reverse or ameliorate the effects of Pompe disease. Included in this proposal are two studies aimed to establish the efficacy and degree of correction utilizing recombinant adeno-associated viral (rAAV)-mediated delivery of GAA in an animal model of Pompe disease.
Specific Aims : 1) To test the hypothesis that systemic delivery of rAAV encoding hGAA attenuates cardioskeletal myopathy;2) To test the hypothesis that administration of rAAV2/9-hGAA therapy in an aged animal model will result in correction of advanced stages of Pompe disease. Taken together, the proposed work will provide new insights into the manner in which gene therapy can correct GAA deficient tissue. Aside from its relevance to patients with Pompe disease, this work will have a profound impact by offering a novel therapeutic option to patients who present alternative cardiovascular and skeletal muscle disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL095282-03
Application #
8136677
Study Section
Special Emphasis Panel (ZRG1-F10-S (21))
Program Officer
Meadows, Tawanna
Project Start
2009-09-08
Project End
2012-05-31
Budget Start
2011-09-08
Budget End
2012-05-31
Support Year
3
Fiscal Year
2011
Total Cost
$42,101
Indirect Cost
Name
University of Florida
Department
Pediatrics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Falk, Darin J; Mah, Cathryn S; Soustek, Meghan S et al. (2013) Intrapleural administration of AAV9 improves neural and cardiorespiratory function in Pompe disease. Mol Ther 21:1661-7
ElMallah, Mai K; Falk, Darin J; Lane, Michael A et al. (2012) Retrograde gene delivery to hypoglossal motoneurons using adeno-associated virus serotype 9. Hum Gene Ther Methods 23:148-56
Byrne, Barry J; Falk, Darin J; Clément, Nathalie et al. (2012) Gene therapy approaches for lysosomal storage disease: next-generation treatment. Hum Gene Ther 23:808-15
Qiu, Kai; Falk, Darin J; Reier, Paul J et al. (2012) Spinal delivery of AAV vector restores enzyme activity and increases ventilation in Pompe mice. Mol Ther 20:21-7
Byrne, Barry J; Falk, Darin J; Pacak, Christina A et al. (2011) Pompe disease gene therapy. Hum Mol Genet 20:R61-8
Soustek, Meghan S; Falk, Darin J; Mah, Cathryn S et al. (2011) Characterization of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency. Hum Gene Ther 22:865-71
Mah, Cathryn S; Falk, Darin J; Germain, Sean A et al. (2010) Gel-mediated delivery of AAV1 vectors corrects ventilatory function in Pompe mice with established disease. Mol Ther 18:502-10