376. Correction of Metabolic Abnormalities in Murine Glycogen Storage Disease Type Ib by Gene Therapy

Glycogen storage disease type Ib (GSD-Ib) is an autosomal recessive disorder caused by deficiencies in a glucose-6-phosphate (G6P) transporter (G6PT) that transloacates G6P from the cytoplasm into the lumen of the endoplasmic reticulum where it is hydrolyzed to glucose and phosphate by the glucose-6-phosphatase-α (G6Pase-α or G6PC) enzyme. The functional coupling of G6PT and G6Pase-α maintains interprandial blood glucose homeostasis. GSD-Ib patients manifest impaired glucose homeostasis characterized by fasting hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation. The current dietary therapies enable patients to maintain normoglycemia but the underlying pathological processes remain uncorrected and long-term complications, including hepatocellular adenoma (HCA), are common. In this study, we examined the efficacy of liver G6PT delivery mediated by two human G6PT-expressing recombinant adeno-associated virus (AAV) pseudotype 2/8 (rAAV8) vectors. One is a single-stranded vector containing a 2864-bp of the human G6PC promoter/enhancer (rAAV8-GPE-G6PT) and the other is a double-stranded vector containing the minimal human G6PT promoter/enhancer (rAAV8-miGT-G6PT). GSD-Ib mice were infused with either vector neonatally, then at age 4 weeks, and metabolic profiles of the infused animals were monitored at age 12 weeks. We show that the rAAV8-GPE-G6PT vector directed significantly higher levels of hepatic G6PT expression, achieved greater reduction in hepatomegaly, and led to a better toleration of fasting in GSD-Ib mice than the rAAV8-miGT-G6PT vector. Our results suggest that the rAAV8-GPE-G6PT vector is an efficacious vector in correcting metabolic abnormalities in murine GSD-Ib.