Correction of multiple striated muscles in murine Pompe disease through adeno-associated virus-mediated gene therapy.
Published
Journal Article
Glycogen storage disease type II (Pompe disease; MIM 232300) stems from the deficiency of acid alpha-glucosidase (GAA; acid maltase; EC 3.2.1.20), which primarily involves cardiac and skeletal muscles. An adeno-associated virus 2/8 (AAV2/8) vector containing the muscle creatine kinase (MCK) (CK1) reduced glycogen content by approximately 50% in the heart and quadriceps in GAA-knockout (GAA-KO) mice; furthermore, an AAV2/8 vector containing the hybrid alpha-myosin heavy chain enhancer-/MCK enhancer-promoter (MHCK7) cassette reduced glycogen content by >95% in heart and >75% in the diaphragm and quadriceps. Transduction with an AAV2/8 vector was higher in the quadriceps than in the gastrocnemius. An AAV2/9 vector containing the MHCK7 cassette corrected GAA deficiency in the distal hindlimb, and glycogen accumulations were substantially cleared by human GAA (hGAA) expression therein; however, the analogous AAV2/7 vector achieved much lower efficacy. Administration of the MHCK7-containing vectors significantly increased striated muscle function as assessed by increased Rotarod times at 18 weeks after injection, whereas the CK1-containing vector did not increase Rotarod performance. Importantly, type IIb myofibers in the extensor digitalis longus (EDL) were transduced, thereby correcting a myofiber type that is unresponsive to enzyme replacement therapy. In summary, AAV8 and AAV9-pseudotyped vectors containing the MHCK7 regulatory cassette achieved enhanced efficacy in Pompe disease mice.
Full Text
Duke Authors
Cited Authors
- Sun, B; Young, SP; Li, P; Di, C; Brown, T; Salva, MZ; Li, S; Bird, A; Yan, Z; Auten, R; Hauschka, SD; Koeberl, DD
Published Date
- August 2008
Published In
Volume / Issue
- 16 / 8
Start / End Page
- 1366 - 1371
PubMed ID
- 18560415
Pubmed Central ID
- 18560415
Electronic International Standard Serial Number (EISSN)
- 1525-0024
Digital Object Identifier (DOI)
- 10.1038/mt.2008.133
Language
- eng
Conference Location
- United States