Efficacy of an adeno-associated virus 8-pseudotyped vector in glycogen storage disease type II.

Abstract

Glycogen storage disease type II (GSD-II; Pompe disease) causes death in infancy from cardiorespiratory failure. The underlying deficiency of acid alpha-glucosidase (GAA; acid maltase) can be corrected by liver-targeted gene therapy in GSD-II, if secretion of GAA is accompanied by receptor-mediated uptake in cardiac and skeletal muscle. An adeno-associated virus (AAV) vector encoding human (h) GAA was pseudotyped as AAV8 (AAV2/8) and injected intravenously into immunodeficient GSD-II mice. High levels of hGAA were maintained in plasma for 24 weeks following AAV2/8 vector administration. A marked increase in vector copy number in the liver was demonstrated for the AAV2/8 vector compared to the analogous AAV2/2 vector. GAA deficiency in the heart and skeletal muscle was corrected with the AAV2/8 vector in male GSD-II mice, consistent with receptor-mediated uptake of hGAA. Male GSD-II mice demonstrated complete correction of glycogen storage in heart and diaphragm with the AAV2/8 vector, while female GSD-II mice had correction only in the heart. A biomarker for GSD-II was reduced in both sexes following AAV2/8 vector administration. Therefore, GAA production with an AAV2/8 vector in a depot organ, the liver, generated evidence for efficacious gene therapy in a mouse model for GSD-II.

• Authors: Baodong Sun, Haoyue Zhang, Luis M Franco, Sarah P Young, Ayn Schneider, Andrew Bird, Andrea Amalfitano, Y-T Chen, Dwight D Koeberl
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 11 Issue 1 Pg. 57-65 (Jan 2005) ISSN: 1525-0016 [Print] United States
• PMID: 15585406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• alpha-Glucosidases
• Glucan 1,4-alpha-Glucosidase
• Glucose

Topics

• Animals
• Cell Line
• Dependovirus (genetics)
• Female
• Gene Expression Regulation
• Genetic Therapy (instrumentation, methods)
• Genetic Vectors (genetics)
• Glucan 1,4-alpha-Glucosidase (administration & dosage, genetics, metabolism)
• Glucose (chemistry, metabolism)
• Glycogen Storage Disease Type II (enzymology, genetics, therapy)
• Humans
• Male
• Mice
• Mice, Knockout
• Motor Activity
• Sex Characteristics
• alpha-Glucosidases