Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors.
Glycogen storage disease type II (GSDII) is caused by a lack of functional lysosomal acid alpha-glucosidase (GAA). Affected individuals store glycogen in lysosomes beginning during gestation, ultimately resulting in fatal hypertrophic cardiomyopathy and respiratory failure. We have assessed the utility of recombinant adeno-associated virus (rAAV) vectors to restore GAA activity in vivo in a mouse model of GSDII (Gaa(-/-)). A single systemic administration of a rAAV serotype 1 (rAAV1) vector to neonate animals resulted in restored cardiac GAA activity to 6.4 times the normal level (mean=641+/-190% of normal (Gaa(+/+)) levels with concomitant glycogen clearance) at 11 months postinjection. Greater than 20% of normal levels of GAA activity were also observed in the diaphragm and quadriceps muscles. Furthermore, functional correction of the soleus skeletal muscle was also observed compared to age-matched untreated Gaa(-/-) control animals. These results demonstrate that rAAV1 vectors can mediate sustained therapeutic levels of correction of both skeletal and cardiac muscles in a model of fatal cardiomyopathy and muscular dystrophy.
Mah
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Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL 32610-0296, USA.
Cresawn
K O
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Fraites
T J
TJ
Pacak
C A
CA
Lewis
M A
MA
Zolotukhin
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Byrne
B J
BJ
D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D003964:Diaphragm / Q000201:enzymology; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D005087:Glucan 1,4-alpha-Glucosidase / Q000235:genetics* / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000201:enzymology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D014161:Transduction, Genetic / Q000379:methods*; D000520:alpha-Glucosidases
D000520:alpha-Glucosidases; D005087:Glucan 1,4-alpha-Glucosidase