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Therapeutic Benefit of Autophagy Modulation in Pompe Disease.

Publication ,  Journal Article
Lim, J-A; Sun, B; Puertollano, R; Raben, N
Published in: Mol Ther
July 5, 2018

The complexity of the pathogenic cascade in lysosomal storage disorders suggests that combination therapy will be needed to target various aspects of pathogenesis. The standard of care for Pompe disease (glycogen storage disease type II), a deficiency of lysosomal acid alpha glucosidase, is enzyme replacement therapy (ERT). Many patients have poor outcomes due to limited efficacy of the drug in clearing muscle glycogen stores. The resistance to therapy is linked to massive autophagic buildup in the diseased muscle. We have explored two strategies to address the problem. Genetic suppression of autophagy in muscle of knockout mice resulted in the removal of autophagic buildup, increase in muscle force, decrease in glycogen level, and near-complete clearance of lysosomal glycogen following ERT. However, this approach leads to accumulation of ubiquitinated proteins, oxidative stress, and exacerbation of muscle atrophy. Another approach involves AAV-mediated TSC knockdown in knockout muscle leading to upregulation of mTOR, inhibition of autophagy, reversal of atrophy, and efficient cellular clearance on ERT. Importantly, this approach reveals the possibility of reversing already established autophagic buildup, rather than preventing its development.

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Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

July 5, 2018

Volume

26

Issue

7

Start / End Page

1783 / 1796

Location

United States

Related Subject Headings

  • alpha-Glucosidases
  • Up-Regulation
  • TOR Serine-Threonine Kinases
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • Male
  • Lysosomes
  • Glycogen Storage Disease Type II
  • Glycogen
 

Citation

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Lim, J.-A., Sun, B., Puertollano, R., & Raben, N. (2018). Therapeutic Benefit of Autophagy Modulation in Pompe Disease. Mol Ther, 26(7), 1783–1796. https://doi.org/10.1016/j.ymthe.2018.04.025
Lim, Jeong-A, Baodong Sun, Rosa Puertollano, and Nina Raben. “Therapeutic Benefit of Autophagy Modulation in Pompe Disease.Mol Ther 26, no. 7 (July 5, 2018): 1783–96. https://doi.org/10.1016/j.ymthe.2018.04.025.
Lim J-A, Sun B, Puertollano R, Raben N. Therapeutic Benefit of Autophagy Modulation in Pompe Disease. Mol Ther. 2018 Jul 5;26(7):1783–96.
Lim, Jeong-A., et al. “Therapeutic Benefit of Autophagy Modulation in Pompe Disease.Mol Ther, vol. 26, no. 7, July 2018, pp. 1783–96. Pubmed, doi:10.1016/j.ymthe.2018.04.025.
Lim J-A, Sun B, Puertollano R, Raben N. Therapeutic Benefit of Autophagy Modulation in Pompe Disease. Mol Ther. 2018 Jul 5;26(7):1783–1796.

Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

July 5, 2018

Volume

26

Issue

7

Start / End Page

1783 / 1796

Location

United States

Related Subject Headings

  • alpha-Glucosidases
  • Up-Regulation
  • TOR Serine-Threonine Kinases
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • Male
  • Lysosomes
  • Glycogen Storage Disease Type II
  • Glycogen