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Correction of glycogen storage disease type 1a in a mouse model by gene therapy

  1. Author:
    Zingone, A.
    Hiraiwa, H.
    Pan, C. J.
    Lin, B. C.
    Chen, H. W.
    Ward, J. M.
    Chou, J. Y.

  2. Author Address

    Chou JY NICHD, Heritable Disorders Branch, NIH Bldg 10,Rm 9S241 Bethesda, MD 20892 USA NICHD, Heritable Disorders Branch, NIH Bethesda, MD 20892 USA Acad Sinica, Inst Biol Chem Taipei Taiwan NCI, Frederick Canc Res & Dev Ctr, Vet & Tumor Pathol Sect,Off Lab Anim Sci, NIH Frederick, MD 21702 USA
    1. Year: 2000
  2. Journal: Journal of Biological Chemistry
    1. 275
    2. 2
    3. Pages: 828-832
  4. Type of Article: Article
  1. Abstract:

    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. [References: 23]

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