909. Sustained Correction of Glycogen Storage Disease Type II by rAAV1 Vector-Mediated Gene Therapy

Abstract

Top of pageAbstract Glycogen storage disease type II (GSDII), is a lysosomal storage disease caused by a partial to complete deficiency in the lysosomal hydrolase, acid |[alpha]|-glucosidase (GAA). From gestation, affected individuals store glycogen in their lysosomal compartments, resulting in severe hypertrophic cardiomyopathy and respiratory insufficiency. Previous studies with intrahepatic and intramuscular delivery of recombinant adeno-associated viral (rAAV) vectors to GSDII mice resulted in a variable anti-GAA immune response and insufficient levels of circulating protein in immune-responsive mice. In this study, we evaluated the potential for intravenously delivered rAAV vectors to correct the biochemical, histological and functional phenotype in GSDII mice over a sustained period of time. Neonatal GSDII mice were intravenously administered 5 |[times]| 1010 particles of rAAV serotype 1 vector encoding human GAA under control of the CMV promoter and analyzed at 2.5, 6 and 11 months post-injection (PI). GAA levels in the heart and diaphragm peaked at 6 months PI with averages of 42 |[plusmn]| 23-fold and 1.4 |[plusmn]| 0.6-fold normal respectively. At 11 months PI, cardiac levels dropped but remained therapeutic at 6.4 |[plusmn]| 1.9-fold normal and these levels were concomitant with glycogen clearance in the heart. Additionally, at 11 months, PI, contractile function of hind-limb muscles was significantly improved and the observed mobility of the treated animals was improved compared to age-matched mice. Six of the 26 treated mice formed anti-GAA antibodies between 4 and 10 weeks PI that quickly dropped to background levels by 15 weeks PI. Based on historical data, the therapeutic target for GAA restoration is 20-30% of normal. In this study, we achieved long-term therapeutic levels of correction from a single intravenous delivery in the two most critically affected muscles, the heart and diaphragm, with functional correction in the skeletal muscle. These results demonstrate the utility of intravenously administered rAAV1 vectors for both skeletal and cardiac muscle gene transfer in a model of fatal cardiomyopathy.