Long-term correction of murine glycogen storage disease type Ia by recombinant adeno-associated virus-1-mediated gene transfer

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Abstract
Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α), a nine-transmembrane domain, endoplasmic reticulum-associated protein expressed primarily in the liver and kidney. Previously, we showed that infusion of an adeno-associated virus (AAV) serotype 2 vector carrying murine G6Pase-α (AAV2-G6Pase-α) into neonatal GSD-Ia mice failed to sustain their life beyond weaning. We now show that neonatal infusion of GSD-Ia mice with an AAV serotype 1-G6Pase-α (AAV1-G6Pase-α) or AAV serotype 8-G6Pase-α (AAV8-G6Pase-α) results in hepatic expression of the G6Pase-α transgene and markedly improves the survival of the mice. However, only AAV1-G6Pase-α can achieve significant renal transgene expression. A more effective strategy, in which a neonatal AAV1-G6Pase-α infusion is followed by a second infusion at age one week, provides sustained expression of a complete, functional, G6Pase-α system in both the liver and kidney and corrects the metabolic abnormalities in GSD-Ia mice for the 57 week length of the study. This effective use of gene therapy to correct metabolic imbalances and disease progression in GSD-Ia mice holds promise for the future of gene therapy in humans.