Skip to main content
Journal cover image

Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high-level vector-mediated transgene expression.

Publication ,  Journal Article
Sun, B; Zhang, H; Bird, A; Li, S; Young, SP; Koeberl, DD
Published in: J Gene Med
October 2009

BACKGROUND: Infantile-onset glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) causes death early in childhood from cardiorespiratory failure in the absence of effective treatment, whereas late-onset Pompe disease causes a progressive skeletal myopathy. The limitations of enzyme replacement therapy could potentially be addressed with adeno-associated virus (AAV) vector-mediated gene therapy. METHODS: AAV vectors containing tissue-specific regulatory cassettes, either liver-specific or muscle-specific, were administered to 12- and 17-month-old Pompe disease mice to evaluate the efficacy of gene therapy in advanced Pompe disease. Biochemical correction was evaluated through acid alpha-glucosidase (GAA) activity and glycogen content analyses of the heart and skeletal muscle. Western blotting, urinary biomarker, and Rotarod performance were evaluated after vector administration. RESULTS: The AAV vector containing the liver-specific regulatory cassette secreted high-level human GAA into the blood and corrected glycogen storage in the heart and diaphragm. The biochemical correction of the heart and diaphragm was associated with efficacy, as reflected by increased Rotarod performance; however, the clearance of glycogen from skeletal muscles was relatively impaired compared to in younger Pompe disease mice. An alternative vector containing a muscle-specific regulatory cassette transduced skeletal muscle with high efficiency, but also failed to achieve complete clearance of accumulated glycogen. Decreased transduction of the heart and liver in older mice, especially in females, was implicated as a cause for reduced efficacy in advanced Pompe disease. CONCLUSIONS: The impaired efficacy of AAV vector-mediated gene therapy in old Pompe disease mice emphasizes the need for early treatment to achieve full efficacy.

Duke Scholars

Published In

J Gene Med

DOI

EISSN

1521-2254

Publication Date

October 2009

Volume

11

Issue

10

Start / End Page

913 / 920

Location

England

Related Subject Headings

  • alpha-Glucosidases
  • Transgenes
  • Sex Factors
  • Muscles
  • Mice
  • Male
  • Lysosomes
  • Liver
  • Humans
  • Glycogen Storage Disease Type II
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Sun, B., Zhang, H., Bird, A., Li, S., Young, S. P., & Koeberl, D. D. (2009). Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high-level vector-mediated transgene expression. J Gene Med, 11(10), 913–920. https://doi.org/10.1002/jgm.1372
Sun, Baodong, Haoyue Zhang, Andrew Bird, Songtao Li, Sarah P. Young, and Dwight D. Koeberl. “Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high-level vector-mediated transgene expression.J Gene Med 11, no. 10 (October 2009): 913–20. https://doi.org/10.1002/jgm.1372.
Sun B, Zhang H, Bird A, Li S, Young SP, Koeberl DD. Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high-level vector-mediated transgene expression. J Gene Med. 2009 Oct;11(10):913–20.
Sun, Baodong, et al. “Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high-level vector-mediated transgene expression.J Gene Med, vol. 11, no. 10, Oct. 2009, pp. 913–20. Pubmed, doi:10.1002/jgm.1372.
Sun B, Zhang H, Bird A, Li S, Young SP, Koeberl DD. Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high-level vector-mediated transgene expression. J Gene Med. 2009 Oct;11(10):913–920.
Journal cover image

Published In

J Gene Med

DOI

EISSN

1521-2254

Publication Date

October 2009

Volume

11

Issue

10

Start / End Page

913 / 920

Location

England

Related Subject Headings

  • alpha-Glucosidases
  • Transgenes
  • Sex Factors
  • Muscles
  • Mice
  • Male
  • Lysosomes
  • Liver
  • Humans
  • Glycogen Storage Disease Type II