350. Kidney-Directed Gene Therapy for Murine Glycogen Storage Disease Type IA

Abstract

Glycogen storage disease type Ia (GSD-Ia, MIM232200) is an autosomal recessive disorder caused by deficiencies in glucose-6-phosphatase-α (G6Pase-α or G6PC) that is expressed primarily in the liver and kidney. GSD-Ia patients manifest impaired glucose homeostasis and a long-term complication of renal disease and there is no existing therapy to address this complication. We have previously shown that systemic administration of rAAV8-G6PC, a rAAV8 vector expressing human G6Pase-α directed by the human G6PC promoter/enhancer, delivers the G6Pase-α transgene to the liver of G6Pase-α-deficient (G6pc-/-) mice and corrects hepatic G6Pase-α deficiency. However, the rAAV8-G6PC vector transduces the kidney poorly and the treated G6pc-/- mice continued manifest renal dysfunction. In this study, we used the rAAV9-G6PC vector in a kidney-targeted gene delivery to improve renal function. The G6pc-/- die early even with glucose therapy. To overcome this, we performed a two-step kidney-directed gene delivery, first neonatally via the temporal vein with rAAV8-G6PC to sustain the survival of the mice, then at 12 weeks of age via retrograde renal vein injection with rAAV9-G6PC. Metabolic profiles and renal function were examined over a 52-week study. The rAAV-treated G6pc-/- mice exhibited normal fasting glucose profiles and could sustain a 24 hour of fast. Moreover, the treated G6pc-/- mice displayed normalized blood urea nitrogen concentrations, indicative of improved renal function. Our results strongly suggest that kidney-directed gene delivery with the rAAV9-G6PC vectors offers a promising and efficacious treatment for renal disease in GSD-Ia.