Journal
MOLECULAR THERAPY
Volume 16, Issue 8, Pages 1366-1371Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2008.133
Keywords
-
Categories
Funding
- NHLBI NIH HHS [R01 HL081122, R01 HL081122-01A1, R24 HL064387, R01 HL081122-02, R01 HL081122-03, R24 HL64387] Funding Source: Medline
- NIAMS NIH HHS [R01 AR18860, R01 AR018860] Funding Source: Medline
- NICHD NIH HHS [1 U54 HD047175, U54 HD047175] Funding Source: Medline
Ask authors/readers for more resources
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 similar to 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available