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Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β2-Agonist in Murine Pompe Disease.

Publication ,  Journal Article
Han, S-O; Li, S; Bird, A; Koeberl, D
Published in: Hum Gene Ther
November 2015

Pompe disease (glycogen storage disease type II; acid maltase deficiency) is a devastating myopathy resulting from acid α-glucosidase (GAA) deficiency in striated and smooth muscle. Despite the availability of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the limitations of ERT have prompted the preclinical development of gene therapy. Gene therapy has the advantage of continuously producing GAA, in contrast to ERT, which requires frequent injections of rhGAA. An adeno-associated viral (AAV) vector containing a muscle-specific promoter, AAV-MHCK7hGAApA, achieved high GAA expression in heart and skeletal muscle in mice with Pompe disease. However, elevated GAA activity was not sufficient to completely clear accumulated glycogen in skeletal muscle. The process of glycogen clearance from lysosomes might require improved trafficking of GAA to the lysosomes in skeletal muscle, previously achieved with the β(2)-agonist clenbuterol that enhanced glycogen clearance in skeletal muscle without increasing GAA activity. Glycogen clearance was clearly enhanced by treatment with a nondepleting anti-CD4 monoclonal antibody (anti-CD4 mAb) along with muscle-specific GAA expression in cardiac muscle, but that treatment was not effective in skeletal muscle. Furthermore, anti-CD4 mAb treatment along with clenbuterol achieved synergistic therapeutic efficacy in both cardiac and skeletal muscle. This triple therapy increased both muscle strength and weight gain. Overall, triple therapy to enhance GAA trafficking and to suppress immune responses significantly improved the efficacy of muscle-targeted gene therapy in murine Pompe disease.

Duke Scholars

Published In

Hum Gene Ther

DOI

EISSN

1557-7422

Publication Date

November 2015

Volume

26

Issue

11

Start / End Page

743 / 750

Location

United States

Related Subject Headings

  • alpha-Glucosidases
  • Recombinant Proteins
  • Myocytes, Cardiac
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • Immune Tolerance
  • Glycogen Storage Disease Type II
  • Glycogen
  • Genetic Therapy
 

Citation

APA
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ICMJE
MLA
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Han, S.-O., Li, S., Bird, A., & Koeberl, D. (2015). Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β2-Agonist in Murine Pompe Disease. Hum Gene Ther, 26(11), 743–750. https://doi.org/10.1089/hum.2015.033
Han, Sang-oh, Songtao Li, Andrew Bird, and Dwight Koeberl. “Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β2-Agonist in Murine Pompe Disease.Hum Gene Ther 26, no. 11 (November 2015): 743–50. https://doi.org/10.1089/hum.2015.033.
Han S-O, Li S, Bird A, Koeberl D. Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β2-Agonist in Murine Pompe Disease. Hum Gene Ther. 2015 Nov;26(11):743–50.
Han, Sang-oh, et al. “Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β2-Agonist in Murine Pompe Disease.Hum Gene Ther, vol. 26, no. 11, Nov. 2015, pp. 743–50. Pubmed, doi:10.1089/hum.2015.033.
Han S-O, Li S, Bird A, Koeberl D. Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β2-Agonist in Murine Pompe Disease. Hum Gene Ther. 2015 Nov;26(11):743–750.
Journal cover image

Published In

Hum Gene Ther

DOI

EISSN

1557-7422

Publication Date

November 2015

Volume

26

Issue

11

Start / End Page

743 / 750

Location

United States

Related Subject Headings

  • alpha-Glucosidases
  • Recombinant Proteins
  • Myocytes, Cardiac
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • Immune Tolerance
  • Glycogen Storage Disease Type II
  • Glycogen
  • Genetic Therapy