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Minimum Effective Dose to Achieve Biochemical Correction with Adeno-Associated Virus Vector-Mediated Gene Therapy in Mice with Pompe Disease.

Publication ,  Journal Article
Han, S-O; Gheorghiu, D; Li, S; Kang, HR; Koeberl, D
Published in: Hum Gene Ther
May 2022

Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA), resulting in skeletal muscle weakness and cardiomyopathy. Muscle weakness progresses despite currently available therapy, which has prompted the development of gene therapy with adeno-associated virus (AAV) type 2 vectors cross-packaged as AAV8 (2/8). Preclinical studies of gene therapy demonstrated that the minimum effective dose (MED) for biochemical correction with AAV2/8-LSPhGAA was ∼2 × 1011 vector genomes (vg)/kg body weight. The current study examined the transduction of AAV2/8-LSPeGFP vector in adult GAA-KO mice with Pompe disease, and correlated that degree of transduction with the biochemical correction achieved by the same dose of AAV2/8-LSPhGAA. The MED was found to be ∼2 × 1011 vg/kg, with all hepatocytes variably transducing at this dose. At this dose, liver GAA significantly increased, while liver glycogen significantly decreased. The 2 × 1011 vg/kg dose was sufficient to significantly decrease diaphragm glycogen. However, the heart, diaphragm, and quadriceps all required a fourfold higher dose to achieve correction of GAA deficiency in association with significant clearance of stored glycogen, which correlated with increased serum GAA activity. These data indicate that AAV2/8-LSPeGFP transduced all hepatocytes when the 2 × 1011 vg/kg dose was administered, which correlated with partial biochemical correction from the equivalent dose of AAV2/8-LSPhGAA. Altogether, these data support the conclusion that substantial transduction of the liver is required to achieve biochemical correction from AAV2/8-LSPhGAA.

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Published In

Hum Gene Ther

DOI

EISSN

1557-7422

Publication Date

May 2022

Volume

33

Issue

9-10

Start / End Page

492 / 498

Location

United States

Related Subject Headings

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

Citation

APA
Chicago
ICMJE
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Han, S.-O., Gheorghiu, D., Li, S., Kang, H. R., & Koeberl, D. (2022). Minimum Effective Dose to Achieve Biochemical Correction with Adeno-Associated Virus Vector-Mediated Gene Therapy in Mice with Pompe Disease. Hum Gene Ther, 33(9–10), 492–498. https://doi.org/10.1089/hum.2021.252
Han, Sang-Oh, Dorothy Gheorghiu, Songtao Li, Hye Ri Kang, and Dwight Koeberl. “Minimum Effective Dose to Achieve Biochemical Correction with Adeno-Associated Virus Vector-Mediated Gene Therapy in Mice with Pompe Disease.Hum Gene Ther 33, no. 9–10 (May 2022): 492–98. https://doi.org/10.1089/hum.2021.252.
Han, Sang-Oh, et al. “Minimum Effective Dose to Achieve Biochemical Correction with Adeno-Associated Virus Vector-Mediated Gene Therapy in Mice with Pompe Disease.Hum Gene Ther, vol. 33, no. 9–10, May 2022, pp. 492–98. Pubmed, doi:10.1089/hum.2021.252.
Han S-O, Gheorghiu D, Li S, Kang HR, Koeberl D. Minimum Effective Dose to Achieve Biochemical Correction with Adeno-Associated Virus Vector-Mediated Gene Therapy in Mice with Pompe Disease. Hum Gene Ther. 2022 May;33(9–10):492–498.
Journal cover image

Published In

Hum Gene Ther

DOI

EISSN

1557-7422

Publication Date

May 2022

Volume

33

Issue

9-10

Start / End Page

492 / 498

Location

United States

Related Subject Headings

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