911. Comparison of rAAV Serotype, Promoter, and Treatment Age for the Correction of Glycogen Storage Disease Type II

Abstract

Glycogen storage disease type II is a prototypical lysosomal storage disease caused by a deficiency in the enzyme acid -glucosidase (GAA). This disorder causes cardiac and skeletal myopathy and respiratory insufficiency. In the most severely affected individuals, GSDII is fatal within 2 years of life. In effort to achieve optimal levels of transgene expression in the affected cardiac and skeletal muscles, we evaluated 3 recombinant adeno-associated viral (rAAV) vectors expressing human GAA (hGAA); rAAV1- and rAAV8-hGAA under control of the CMV promoter and rAAV8-hGAA under control of a liver specific promoter (LSP). These vectors were delivered to both neonatal and adult GSDII mice. In general, treatment of neonatal mice was more successful than adult mice and serotype 8 vectors resulted in higher expression levels than serotype 1 vectors. At 10 wks post-injection (PI), rAAV8-CMV-hGAA- treated mice had 2.8-fold higher levels of GAA activity in the heart and 10.5-fold higher levels in the diaphragm compared to rAAV1-CMV-hGAA- treated mice (with averages of 45-fold normal and 8.7-fold normal in the respective tissues of rAAV8-treated mice). GAA activity in the hind-limb muscles was also significantly improved in rAAV8-treated mice with up to 83 30% of normal GAA activity in the tibialis anterior muscle. In neonatal mice treated with rAAV8-LSP-hGAA, GAA levels gradually dropped from 1 to 10 wks PI, which was attributed to the progressive loss of vector genomes in the transduced neonatal liver.