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

Abstract

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.

• Authors: Sang-Oh Han, Dorothy Gheorghiu, Songtao Li, Hye Ri Kang, Dwight Koeberl
• Journal: Human gene therapy (Hum Gene Ther) Vol. 33 Issue 9-10 Pg. 492-498 (05 2022) ISSN: 1557-7422 [Electronic] United States
• PMID: 35102744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glycogen
• alpha-Glucosidases

Topics

• Animals
• Dependovirus (genetics)
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Glycogen
• Glycogen Storage Disease Type II (genetics, therapy)
• Mice
• Mice, Knockout
• Muscle, Skeletal
• alpha-Glucosidases (genetics)