The goal of this K01 Award application is to enhance the academic and scientific development of the Candidate, Dr. Falk. Under the guidance of Drs. Barry Byrne, Lucia Notterpek, David Fuller, and Scott Rivkees, the Candidate will pursue the link between respiratory insufficiency and the pathologic adaptations of axons, the neuromuscular junction, and skeletal muscle in Pompe disease. Pompe disease is a progressive disorder in which the deficiency or absence of acid alpha-glucosidase (GAA), leads to severe muscle weakness and often-premature death from respiratory muscle failure. The only FDA approved treatment for Pompe disease is enzyme replacement therapy (ERT). While ERT has improved outcomes, patients still suffer from inadequate alveolar ventilation and eventually require ventilatory assistance. Our long-term goal is to determine the mechanisms, which lead to respiratory muscle failure in this patient population. To make a significant shift in the management of care for Pompe patients, we have developed a systematic approach to identify the key mechanisms, which directly impact skeletal muscle activation and regulation. This will be accomplished using transgenic models of Pompe disease and recombinant adeno-associated virus (AAV) vectors. Recently, we observed that abrupt morphologic changes occur at the neuromuscular junction and may be key in elucidating the primary mechanism behind respiratory dysfunction. This application will focus on the role of the neuromuscular junction (NMJ) and potential therapies to restore skeletal muscle activation and function in Pompe disease. We will accomplish this by: 1) determining the negative impact at the neuromuscular junction as a result of CNS and skeletal muscle glycogen accumulation, 2) we will determine if skeletal muscle force production is primarily impaired due to pathologic adaptations in neurons and the neuromuscular junction in Pompe mice, and 3) directly compare existing and novel therapies to reduce glycogen deposition in critical tissues and ultimately restore respiratory and locomotor function in Pompe patients. In this regard, the specific aims seek to address several potential mechanisms for improving our overall understanding of the pathogenesis of Pompe disease and provide a platform for future research and funding to initiate an independent career centered on neuromuscular disease.

Public Health Relevance

Pompe disease is associated with progressive accumulation of lysosomal glycogen and leads to respiratory insufficiency in the patient population. Recent evidence suggests the neuromuscular synapse may be affected and contributes to respiratory problems. This proposal will help identify novel targets for therapeutic intervention to attenuate neuromuscular failure in Pompe patients.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Scientist Development Award - Research & Training (K01)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Boyce, Amanda T
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University of Florida
Schools of Medicine
United States
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Baligand, Celine; Todd, Adrian G; Lee-McMullen, Brittany et al. (2017) 13C/31P MRS Metabolic Biomarkers of Disease Progression and Response to AAV Delivery of hGAA in a Mouse Model of Pompe Disease. Mol Ther Methods Clin Dev 7:42-49
Turner, S M F; Falk, D J; Byrne, B J et al. (2016) Transcriptome assessment of the Pompe (Gaa-/-) mouse spinal cord indicates widespread neuropathology. Physiol Genomics 48:785-794
Doerfler, Phillip A; Todd, Adrian G; Clément, Nathalie et al. (2016) Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease. Hum Gene Ther 27:43-59
Adamson-Small, Laura; Potter, Mark; Falk, Darin J et al. (2016) A scalable method for the production of high-titer and high-quality adeno-associated type 9 vectors using the HSV platform. Mol Ther Methods Clin Dev 3:16031
Turner, Sara M F; Hoyt, Aaron K; ElMallah, Mai K et al. (2016) Neuropathology in respiratory-related motoneurons in young Pompe (Gaa(-/-)) mice. Respir Physiol Neurobiol 227:48-55
Todd, Adrian G; McElroy, Jessica A; Grange, Robert W et al. (2015) Correcting Neuromuscular Deficits With Gene Therapy in Pompe Disease. Ann Neurol 78:222-34
Falk, Darin J; Todd, Adrian Gary; Lee, Sooyeon et al. (2015) Peripheral nerve and neuromuscular junction pathology in Pompe disease. Hum Mol Genet 24:625-36
Falk, Darin J; Soustek, Meghan S; Todd, Adrian Gary et al. (2015) Comparative impact of AAV and enzyme replacement therapy on respiratory and cardiac function in adult Pompe mice. Mol Ther Methods Clin Dev 2:15007