Glycogen storage disease type II (GSDII) results from deficiency of acid a-glucosidase (GAA), a lysosomal enzyme that degrades glycogen. GSDII causes cardiorespiratory failure in infants, and progressive respiratory failure in juveniles and adults. Although respiratory failure has been attributed to muscle pathology, autopsy case reports show cervical spinal glycogen accumulation and suggest motoneuron pathology. We have observed that efferent phrenic discharge, mean inspiratory airflow, and the ratio of minute ventilation to metabolic rate (VE/VCO2) are blunted in a murine GSDII model, the GAA-/- """"""""knockout"""""""" mouse. In addition, a selective knockout mouse with normal skeletal muscle contractility and GAA expression, but no GAA in the central nervous system (CNS), also exhibits marked reductions in phrenic output and ventilation. Accordingly, CNS GAA deficiency is associated with impaired respiratory motor output, and respiratory insufficiency in GSDII may reflect both a neural and a muscular pathology. A neural mechanism is also implicated by preliminary data showing extensive cervical spinal glycogen accumulation in GAA-/- mice, particularly within retrogradely identified phrenic motoneurons. Determining the mechanisms underlying respiratory insufficiency is important because i.v. enzyme replacement (the current clinical GSDII therapy) does not target the CNS as GAA cannot cross the blood brain barrier. A promising method for targeting both muscle and the CNS is recombinant adeno-associated virus (rAAV) gene therapy. Our preliminary data indicate that rAAV effectively transfects phrenic motoneurons, and can be delivered by intraspinal or intrathoracic injection. Further, ventilation is significantly enhanced in GAA-/- mice one month following intrathoracic injection of rAAV packaged with the GAA gene (rAAV-GAA therapy). These experiments represent a unique collaboration between laboratories specializing in respiratory physiology (Fuller), gene therapy (Byrne), and neuroanatomy (Reier). We propose to test three hypotheses: 1) neural drive to the diaphragm and ventilation are attenuated in both the selective and full GAA-/- knockout mice; 2) respiratory deficits in these mice occur in parallel with glycogen accumulation in phrenic motoneurons, and 3) intraspinal and intrathoracic rAAV-GAA delivery can ameliorate spinal glycogen accumulation and enhance respiratory motor output in the selective and GAA-/- knockout mice, respectively. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD052682-01A1
Application #
7198932
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Oster-Granite, Mary Lou
Project Start
2007-02-15
Project End
2012-01-31
Budget Start
2007-02-15
Budget End
2008-01-31
Support Year
1
Fiscal Year
2007
Total Cost
$311,313
Indirect Cost
Name
University of Florida
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Keeler, Allison M; Zieger, Marina; Todeasa, Sophia H et al. (2018) Systemic Delivery of AAVB1-GAA Clears Glycogen and Prolongs Survival in a Mouse Model of Pompe Disease. Hum Gene Ther :
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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Fuller, David D; Mitchell, Gordon S (2017) Special Issue: Respiratory Neuroplasticity. Exp Neurol 287:91-92
Keeler, Allison M; Liu, Donghai; Zieger, Marina et al. (2017) Airway smooth muscle dysfunction in Pompe (Gaa-/- ) mice. Am J Physiol Lung Cell Mol Physiol 312:L873-L881
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
Kishnani, Priya; Tarnopolsky, Mark; Roberts, Mark et al. (2017) Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid ?-Glucosidase in Pompe Patients Co-administered with Alglucosidase ?. Mol Ther 25:1199-1208
Corti, Manuela; Liberati, Cristina; Smith, Barbara K et al. (2017) Safety of Intradiaphragmatic Delivery of Adeno-Associated Virus-Mediated Alpha-Glucosidase (rAAV1-CMV-hGAA) Gene Therapy in Children Affected by Pompe Disease. Hum Gene Ther Clin Dev 28:208-218
Smith, Barbara K; Fuller, David D; Martin, A Daniel et al. (2016) Diaphragm Pacing as a Rehabilitative Tool for Patients With Pompe Disease Who Are Ventilator-Dependent: Case Series. Phys Ther 96:696-703

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