title: Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors.
abstract: 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.
authors.affiliation: Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL 32610-0296, USA.
authors.forename: C
authors.initials: C
authors.lastname: Mah
authors.forename: K O
authors.initials: KO
authors.lastname: Cresawn
authors.forename: T J
authors.initials: TJ
authors.lastname: Fraites
authors.forename: C A
authors.initials: CA
authors.lastname: Pacak
authors.forename: M A
authors.initials: MA
authors.lastname: Lewis
authors.forename: I
authors.initials: I
authors.lastname: Zolotukhin
authors.forename: B J
authors.initials: BJ
authors.lastname: Byrne
mesh_terms: 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
chemical_list: D000520:alpha-Glucosidases; D005087:Glucan 1,4-alpha-Glucosidase