Adenovirus-mediated gene therapy in a mouse model of glycogen storage disease type 1a

Glycogen storage disease type 1a (GSD-1a), characterized by growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, and renal dysfunction, is caused by deficiencies in glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis. Over the last 20 years, dietary therapies have greatly improved the prognosis of GSD-1a patients. However, the underlying pathological process remains uncorrected and the efficacy of dietary treatment is frequently limited by poor compliance. Therefore, long-term complications still develop in adult patients. To develop future therapeutic approaches for GSD-1a, we have generated G6Pase-deficient (G6Pase(-/-)) mice that mimic the pathophysiology of human GSD-1a patients. To evaluate the feasibility of gene replacement therapy for this disorder, we have infused recombinant adenovirus containing murine G6Pase gene (Ad-mG6Pase) into G6Pase(-/-) mice. While only 15% of G6Pase(-/-) mice under glucose therapy survived weaning, a 100% survival rate was achieved when G6Pase(-/-) mice were infused with Ad-mG6Pase and 90% of which lived to 3 months of age. Hepatic G6Pase activity in Ad-mG6Pase-infused mice was restored to 19% of that in G6Pase(+/+) mice at 7 through 14 post-infusion days. Ad-mG6Pase infusion also greatly improved growth of G6Pase(-/-) mice and normalized plasma glucose, cholesterol, triglyceride, and uric acid profiles. Further, liver and kidney enlargement were less pronounced with near normal levels of glycogen depositions in both organs. Conclusion: our data demonstrate that a single administration of a recombinant adenovirus vector can alleviate the clinical manifestations of glycogen storage, disease type 1a in mice, suggesting that this disorder in humans can potentially be corrected by gene therapy.