title: 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.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Baodong
authors.initials: B
authors.lastname: Sun
authors.forename: Haoyue
authors.initials: H
authors.lastname: Zhang
authors.forename: Luis M
authors.initials: LM
authors.lastname: Franco
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Young
authors.forename: Ayn
authors.initials: A
authors.lastname: Schneider
authors.forename: Andrew
authors.initials: A
authors.lastname: Bird
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
authors.forename: Y-T
authors.initials: YT
authors.lastname: Chen
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
mesh_terms: D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000295:instrumentation / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics*; D005087:Glucan 1,4-alpha-Glucosidase / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D012727:Sex Characteristics; D000520:alpha-Glucosidases
chemical_list: D000520:alpha-Glucosidases; D005087:Glucan 1,4-alpha-Glucosidase; D005947:Glucose