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J Biol Chem, Vol. 275, Issue 2, 828-832, January 14, 2000

Correction of Glycogen Storage Disease Type 1a in a Mouse Model by Gene Therapy^*

Adriana Zingone, Hisayuki Hiraiwa, Chi-Jiunn Pan, Baochuan Lin, Hungwen Chen^§, Jerrold M. Ward^¶, and Janice Yang Chou

From the  Heritable Disorders Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892-1830, the ^§ Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China, and the ^¶ Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, NCI-Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702

Glycogen storage disease type 1a (GSD-1a), characterized by hypoglycemia, liver and kidney enlargement, growth retardation, hyperlipidemia, and hyperuricemia, is caused by a deficiency in glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis. To evaluate the feasibility of gene replacement therapy for GSD-1a, we have infused adenoviral vector containing the murine G6Pase gene (Ad-mG6Pase) into G6Pase-deficient (G6Pase^/) mice that manifest symptoms characteristic of human GSD-1a. Whereas <15% of G6Pase^/ mice under glucose therapy survived weaning, a 100% survival rate was achieved when G6Pase^/ mice were infused with Ad-mG6Pase, 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 7-14 days post-infusion; the activity persisted for at least 70 days. Ad-mG6Pase infusion also greatly improved growth of G6Pase^/ mice and normalized plasma glucose, cholesterol, triglyceride, and uric acid profiles. Furthermore, liver and kidney enlargement was less pronounced with near-normal levels of glycogen depositions in both organs. Our data demonstrate that a single administration of a recombinant adenoviral vector can alleviate the pathological manifestations of GSD-1a in mice, suggesting that this disorder in humans can potentially be corrected by gene therapy.

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