Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

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 till develop in adult patients. To develop future therapeutic approaches for GSD-1a, we have generatedG6Pase-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 murineG6Pase 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

Ad-mG6Pase :

recombinant adenovirus containing murineG6Pase gene

ER :

endoplasmic reticulum

G6P :

glucose-6-phosphate

G6 Pase :

glucose-6-phosphatase

GSD-1a :

glycogen storage disease type 1a

References

  1. Arden SD, Zahn T, Steegers S, Webb S, Bergman B, O'Brien, RM, Hutton JC (1999) Molecular cloning of a pancreatic isletspecific glucose-6-phosphatase catalytic subunit-related protein. Diabetes 48: 531–542

    Article  CAS  PubMed  Google Scholar 

  2. Arion WJ, Lange AJ, Walls HE, Ballas LM (1980) Evidence of the participation of independent translocases for phosphate and glucose-6-phosphate in the microsomal glucose-6-phosphatase system. J Biol Chem. 255: 10396–10406

    CAS  PubMed  Google Scholar 

  3. Chen Y-T, Burchell A (1995) Glycogen storage diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 935–965

    Google Scholar 

  4. Chou JY (2001) Molecular basic of type 1 glycogen storage disease. Curr Mol Med 1: 25–44

    Article  CAS  PubMed  Google Scholar 

  5. Chou JY, Mansfield BC (1999) Molecular genetics of type 1 glycogen storage diseases. Trend Endocrinol Metab 10: 104–113

    Article  CAS  Google Scholar 

  6. Hemrika W, Renirie R, Dekker HL, Barnett P, Wever R (1997) From phosphatases to vanadium peroxidases: a similar architecture of the active site. Proc Natl Acad Sci U S A 94: 2145–2149

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Kirschner BS, Baker AL, Thorp FK (1991) Growth in adulthood after liver transplantation for glycogen storage disease type I. Gastroenterology 101: 238–241.

    CAS  PubMed  Google Scholar 

  8. Kozarsky KF, Wilson JM (1993) Gene therapy; adenovirus vectors. Curr Opin Genet Dev 3: 499–503

    Article  CAS  PubMed  Google Scholar 

  9. Lei K-J, Shelly LL, Pan C-J, Sidbury JB, Chou JY (1993) Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science 262: 580–583

    Article  CAS  PubMed  Google Scholar 

  10. Lei K-J, Shelly LL, Pan C-J, Liu J-L, Chou JY (1995) Structure-function analysis of human glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1a. J Biol Chem 270: 11882–11886.

    Article  CAS  PubMed  Google Scholar 

  11. Lei K-J, Chen H, Pan C-J, Ward JM, Mosinger B, Lee EJ, Westphal H, Manfsfield BC, Chou JY (1996) Glucose-6-phosphatase dependent substrate transport in the glycogen storage disease type 1a mouse. Nat Genet 13: 203–209

    Article  CAS  PubMed  Google Scholar 

  12. Mittereder N, Yei S, Bachurski C, Cuppoletti J, Whttsett JA, Tolstochev P, Trapnell BC (1994) Evaluation of the efficacy and safety of in vitro, adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator cDNA. Hum Gene Ther 5: 719–731

    Article  Google Scholar 

  13. Nordlie RC, Sukalski KA (1985) Multifunctional, glucose-6-phosphatase: a critical review. In: Martosoni AN (ed) The enzymes of biological membranes, 2nd edn. Plenum, New York, pp 349–398

    Chapter  Google Scholar 

  14. Pan C-J, Lei K-J, Chou JY (1998) Asparagine-linked oligosaccharides are localized to a luminal hydrophilic loop in human glucose-6-phosphatase. J Biol Chem 273: 21658–21662

    Article  CAS  PubMed  Google Scholar 

  15. Pan C-J, Lei K-J, Annabi B, Hemrika W, Chou JY (1998). Transmembrane topology of glucose-6-phosphatase. J Biol Chem 273: 6144–6148

    Article  CAS  PubMed  Google Scholar 

  16. Pan C-J, Lei K-J, Chen H, Ward JM, Chou JY (1998) Ontogeny of the murine glucose-6-phosphatase system. Arch Biochem Biophys 358: 17–24.

    Article  CAS  PubMed  Google Scholar 

  17. Selby R, Starzl TE, Yunis E, Todo S, Tzakis AG, Brown BI, Kendall RS (1993) Liver transplantation for type I and type IV glycogen storage disease. Eur J Pediatr 152[Suppl 1]: S71-S76

    Article  PubMed Central  PubMed  Google Scholar 

  18. Shelly LL, Lei K-J, Pan C-J, Sakata SF, Ruppert S, Schutz G, Chou JY (1993) Isolation of the gene for murine glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1a. J Biol Chem 268: 21482–21485

    CAS  PubMed  Google Scholar 

  19. Stratford-Perricaudet LD, Perricaudet M (1991) Gene therapy: the advent of adenovirus. In: Wolff JA (ed) Gene therapeutics: methods and applications of direct gene transfer. Birkhauser, Boston, pp 345–362

    Google Scholar 

  20. Trapnell BC (1993) Adenoviral vectors for gene transfer. Adv Drug Delivery Rev 12: 185–199

    Article  CAS  Google Scholar 

  21. Yang Y, Nunes FA, Berencsi K, Gonzol E, Engelhardt JF, Wilson JM (1994) Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis. Nat Genet 7: 362–369.

    Article  CAS  PubMed  Google Scholar 

  22. Zingone A, Hiraiwa H, Pan C-J, Lin B, Ward JM, Chou JY (2000) Correction of glycogen storage disease type 1a in a mouse model by gene therapy. J Biol Chem 275: 828–832

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Heritable Disorders Branch, National Institute of Child Health and Humand Development, NIH, Building 10, Room 9S241, 20892-1830, Bethesda, MD, USA

    Janice Yang Chou, Adriana Zingone & Chi-Jiunn Pan

Authors
  1. Janice Yang Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adriana Zingone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chi-Jiunn Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Janice Yang Chou.

Additional information

Published online: 19 July 2002

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chou, J.Y., Zingone, A. & Pan, CJ. Adenovirus-mediated gene therapy in a mouse model of glycogen storage disease type 1a. Eur J Pediatr 161, S56–S61 (2002). https://doi.org/10.1007/BF02679996

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02679996

Keywords

Search

Navigation