title: Long-term correction of glycogen storage disease type II with a hybrid Ad-AAV vector.
abstract: We administered an adenovirus-adeno-associated virus (Ad-AAV) vector encoding human acid alpha-glucosidase (hGAA) to acid alpha-glucosidase-knockout (GAA-KO) mice on day 3 of life by gastrocnemius injection. In contrast to previous results for muscle-targeted Ad vector in adult GAA-KO mice, the muscles of the hindlimb showed reduced glycogen content and persistent hGAA for as long as 6 months after neonatal Ad-AAV vector administration. Not only the injected gastrocnemius muscles, but also the hamstrings and quadriceps muscles produced therapeutic levels of hGAA as a result of widespread transduction with the Ad-AAV vector; moreover, hGAA activity was 50-fold elevated as compared to normal mice. Vector RNA was detected in the hindlimb muscles, the hearts, and the livers by northern blot analysis and/or by RT-PCR for as long as 6 months. The low levels of hGAA detected in the heart were attributable to transduction with the Ad-AAV vector, not to secretion of hGAA by the injected muscle and uptake by the heart. Finally, although an antibody response to hGAA was present, it did not prevent the correction of glycogen storage in the skeletal muscle of GAA-KO mice.
authors.affiliation: Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Bao-dong
authors.initials: BD
authors.lastname: Sun
authors.forename: Y-T
authors.initials: YT
authors.lastname: Chen
authors.forename: Andrew
authors.initials: A
authors.lastname: Bird
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000235:genetics / Q000628:therapy*; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D006003:Glycogen