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Intrapleural administration of AAV9 improves neural and cardiorespiratory function in Pompe disease.

Publication ,  Journal Article
Falk, DJ; Mah, CS; Soustek, MS; Lee, K-Z; Elmallah, MK; Cloutier, DA; Fuller, DD; Byrne, BJ
Published in: Mol Ther
September 2013

Pompe disease is a neuromuscular disease resulting from deficiency in acid α-glucosidase (GAA), results in cardiac, skeletal muscle, and central nervous system (CNS) pathology. Enzyme replacement therapy (ERT) has been shown to partially correct cardiac and skeletal muscle dysfunction. However, ERT does not cross the blood-brain barrier and progressive CNS pathology ensues. We tested the hypothesis that intrapleural administration of recombinant adeno-associated virus (rAAV9)-GAA driven by a cytomegalovirus (CMV) or desmin (DES) promoter would improve cardiac and respiratory function in Gaa(-/-) mice through a direct effect and retrograde transport to motoneurons. Cardiac magnetic resonance imaging revealed significant improvement in ejection fraction in rAAV9-GAA-treated animals. Inspiratory phrenic and diaphragm activity was examined at baseline and during hypercapnic respiratory challenge. Mice treated with AAV9 had greater relative inspiratory burst amplitude during baseline conditions when compared with Gaa(-/-). In addition, efferent phrenic burst amplitude was significantly correlated with diaphragm activity in both AAV9-DES and AAV9-CMV groups but not in Gaa(-/-). This is the first study to indicate improvements in cardiac, skeletal muscle, and respiratory neural output following rAAV administration in Pompe disease. These results further implicate a role for the CNS in Pompe disease pathology and the critical need to target the neurologic aspects in developing therapeutic strategies.

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Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

September 2013

Volume

21

Issue

9

Start / End Page

1661 / 1667

Location

United States

Related Subject Headings

  • alpha-Glucosidases
  • Transduction, Genetic
  • Spinal Cord
  • Respiratory Muscles
  • Random Allocation
  • Pleura
  • Phrenic Nerve
  • Myocardium
  • Muscle, Skeletal
  • Mice
 

Citation

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Falk, D. J., Mah, C. S., Soustek, M. S., Lee, K.-Z., Elmallah, M. K., Cloutier, D. A., … Byrne, B. J. (2013). Intrapleural administration of AAV9 improves neural and cardiorespiratory function in Pompe disease. Mol Ther, 21(9), 1661–1667. https://doi.org/10.1038/mt.2013.96
Falk, Darin J., Cathryn S. Mah, Meghan S. Soustek, Kun-Ze Lee, Mai K. Elmallah, Denise A. Cloutier, David D. Fuller, and Barry J. Byrne. “Intrapleural administration of AAV9 improves neural and cardiorespiratory function in Pompe disease.Mol Ther 21, no. 9 (September 2013): 1661–67. https://doi.org/10.1038/mt.2013.96.
Falk DJ, Mah CS, Soustek MS, Lee K-Z, Elmallah MK, Cloutier DA, et al. Intrapleural administration of AAV9 improves neural and cardiorespiratory function in Pompe disease. Mol Ther. 2013 Sep;21(9):1661–7.
Falk, Darin J., et al. “Intrapleural administration of AAV9 improves neural and cardiorespiratory function in Pompe disease.Mol Ther, vol. 21, no. 9, Sept. 2013, pp. 1661–67. Pubmed, doi:10.1038/mt.2013.96.
Falk DJ, Mah CS, Soustek MS, Lee K-Z, Elmallah MK, Cloutier DA, Fuller DD, Byrne BJ. Intrapleural administration of AAV9 improves neural and cardiorespiratory function in Pompe disease. Mol Ther. 2013 Sep;21(9):1661–1667.

Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

September 2013

Volume

21

Issue

9

Start / End Page

1661 / 1667

Location

United States

Related Subject Headings

  • alpha-Glucosidases
  • Transduction, Genetic
  • Spinal Cord
  • Respiratory Muscles
  • Random Allocation
  • Pleura
  • Phrenic Nerve
  • Myocardium
  • Muscle, Skeletal
  • Mice