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Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase.

Publication ,  Journal Article
Puzzo, F; Colella, P; Biferi, MG; Bali, D; Paulk, NK; Vidal, P; Collaud, F; Simon-Sola, M; Charles, S; Hardet, R; Leborgne, C; Meliani, A ...
Published in: Science translational medicine
November 2017

Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therapy is available for Pompe disease; however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes. Then, we used adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the GAA transgenes to Gaa knockout (Gaa-/-) mice, a model of Pompe disease. Therapeutic gene transfer to the liver rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in the Gaa-/- mice; mouse survival was also increased. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. Scale-up to nonhuman primates, and modeling of GAA expression in primary human hepatocytes using hepatotropic AAV vectors, demonstrated the therapeutic potential of AAV vector-mediated liver expression of secretable GAA for treating pathological glycogen accumulation in multiple tissues in Pompe disease.

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Published In

Science translational medicine

DOI

EISSN

1946-6242

ISSN

1946-6234

Publication Date

November 2017

Volume

9

Issue

418

Start / End Page

eaam6375

Related Subject Headings

  • alpha-Glucosidases
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • Male
  • Liver
  • Glycogen Storage Disease Type II
  • Genetic Vectors
  • Genetic Therapy
  • Dependovirus
 

Citation

APA
Chicago
ICMJE
MLA
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Puzzo, F., Colella, P., Biferi, M. G., Bali, D., Paulk, N. K., Vidal, P., … Mingozzi, F. (2017). Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase. Science Translational Medicine, 9(418), eaam6375. https://doi.org/10.1126/scitranslmed.aam6375
Puzzo, Francesco, Pasqualina Colella, Maria G. Biferi, Deeksha Bali, Nicole K. Paulk, Patrice Vidal, Fanny Collaud, et al. “Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase.Science Translational Medicine 9, no. 418 (November 2017): eaam6375. https://doi.org/10.1126/scitranslmed.aam6375.
Puzzo F, Colella P, Biferi MG, Bali D, Paulk NK, Vidal P, et al. Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase. Science translational medicine. 2017 Nov;9(418):eaam6375.
Puzzo, Francesco, et al. “Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase.Science Translational Medicine, vol. 9, no. 418, Nov. 2017, p. eaam6375. Epmc, doi:10.1126/scitranslmed.aam6375.
Puzzo F, Colella P, Biferi MG, Bali D, Paulk NK, Vidal P, Collaud F, Simon-Sola M, Charles S, Hardet R, Leborgne C, Meliani A, Cohen-Tannoudji M, Astord S, Gjata B, Sellier P, van Wittenberghe L, Vignaud A, Boisgerault F, Barkats M, Laforet P, Kay MA, Koeberl DD, Ronzitti G, Mingozzi F. Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase. Science translational medicine. 2017 Nov;9(418):eaam6375.

Published In

Science translational medicine

DOI

EISSN

1946-6242

ISSN

1946-6234

Publication Date

November 2017

Volume

9

Issue

418

Start / End Page

eaam6375

Related Subject Headings

  • alpha-Glucosidases
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • Male
  • Liver
  • Glycogen Storage Disease Type II
  • Genetic Vectors
  • Genetic Therapy
  • Dependovirus