Correction of multiple striated muscles in murine Pompe disease through adeno-associated virus-mediated gene therapy.
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.
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
Baodong
B
Sun
Sarah P
SP
Young
Ping
P
Li
Chunhui
C
Di
Talmage
T
Brown
Maja Z
MZ
Salva
Songtao
S
Li
Andrew
A
Bird
Zhen
Z
Yan
Richard
R
Auten
Stephen D
SD
Hauschka
Dwight D
DD
Koeberl
D000818:Animals; D052283:Creatine Kinase, MM Form / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000235:genetics / Q000628:therapy*; D006614:Hindlimb / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D054792:Muscle, Striated / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D052097:Quadriceps Muscle / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic; D000520:alpha-Glucosidases / Q000235:genetics / Q000378:metabolism
D006003:Glycogen; D052283:Creatine Kinase, MM Form; D000520:alpha-Glucosidases; D018995:Myosin Heavy Chains