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Sustained correction of motoneuron histopathology following intramuscular delivery of AAV in pompe mice.

Publication ,  Journal Article
Elmallah, MK; Falk, DJ; Nayak, S; Federico, RA; Sandhu, MS; Poirier, A; Byrne, BJ; Fuller, DD
Published in: Mol Ther
April 2014

Pompe disease is an autosomal recessive disorder caused by mutations in the acid-α glucosidase (GAA) gene. Lingual dysfunction is prominent but does not respond to conventional enzyme replacement therapy (ERT). Using Pompe (Gaa(-/-)) mice, we tested the hypothesis that intralingual delivery of viral vectors encoding GAA results in GAA expression and glycogen clearance in both tongue myofibers and hypoglossal (XII) motoneurons. An intralingual injection of an adeno-associated virus (AAV) vector encoding GAA (serotypes 1 or 9; 1 × 10(11) vector genomes, CMV promoter) was performed in 2-month-old Gaa(-/-) mice, and tissues were harvested 4 months later. Both serotypes robustly transduced tongue myofibers with histological confirmation of GAA expression (immunochemistry) and glycogen clearance (Period acid-Schiff stain). Both vectors also led to medullary transgene expression. GAA-positive motoneurons did not show the histopathologic features which are typical in Pompe disease and animal models. Intralingual injection with the AAV9 vector resulted in approximately threefold more GAA-positive XII motoneurons (P < 0.02 versus AAV1); the AAV9 group also gained more body weight over the course of the study (P < 0.05 versus AAV1 and sham). We conclude that intralingual injection of AAV1 or AAV9 drives persistent GAA expression in tongue myofibers and motoneurons, but AAV9 may more effectively target motoneurons.

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Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

April 2014

Volume

22

Issue

4

Start / End Page

702 / 712

Location

United States

Related Subject Headings

  • alpha-Glucosidases
  • Promoter Regions, Genetic
  • Myofibrils
  • Muscle, Skeletal
  • Motor Neurons
  • Mice
  • Injections, Intramuscular
  • Humans
  • Glycogen Storage Disease Type II
  • Glycogen
 

Citation

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Elmallah, M. K., Falk, D. J., Nayak, S., Federico, R. A., Sandhu, M. S., Poirier, A., … Fuller, D. D. (2014). Sustained correction of motoneuron histopathology following intramuscular delivery of AAV in pompe mice. Mol Ther, 22(4), 702–712. https://doi.org/10.1038/mt.2013.282
Elmallah, Mai K., Darin J. Falk, Sushrusha Nayak, Roland A. Federico, Milapjit S. Sandhu, Amy Poirier, Barry J. Byrne, and David D. Fuller. “Sustained correction of motoneuron histopathology following intramuscular delivery of AAV in pompe mice.Mol Ther 22, no. 4 (April 2014): 702–12. https://doi.org/10.1038/mt.2013.282.
Elmallah MK, Falk DJ, Nayak S, Federico RA, Sandhu MS, Poirier A, et al. Sustained correction of motoneuron histopathology following intramuscular delivery of AAV in pompe mice. Mol Ther. 2014 Apr;22(4):702–12.
Elmallah, Mai K., et al. “Sustained correction of motoneuron histopathology following intramuscular delivery of AAV in pompe mice.Mol Ther, vol. 22, no. 4, Apr. 2014, pp. 702–12. Pubmed, doi:10.1038/mt.2013.282.
Elmallah MK, Falk DJ, Nayak S, Federico RA, Sandhu MS, Poirier A, Byrne BJ, Fuller DD. Sustained correction of motoneuron histopathology following intramuscular delivery of AAV in pompe mice. Mol Ther. 2014 Apr;22(4):702–712.

Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

April 2014

Volume

22

Issue

4

Start / End Page

702 / 712

Location

United States

Related Subject Headings

  • alpha-Glucosidases
  • Promoter Regions, Genetic
  • Myofibrils
  • Muscle, Skeletal
  • Motor Neurons
  • Mice
  • Injections, Intramuscular
  • Humans
  • Glycogen Storage Disease Type II
  • Glycogen