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Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia

Gene Therapy volume 19, pages 443–452 (2012)Cite this article

Abstract

Glycogen storage disease type Ia (GSD-Ia) stems from glucose-6-phosphatase (G6Pase) deficiency and causes hypoglycemia, hepatomegaly, hypercholesterolemia and lactic acidemia. Three dogs with GSD-Ia were initially treated with a helper-dependent adenovirus encoding a human G6Pase transgene (HDAd-cG6Pase serotype 5) on postnatal day 3. Unlike untreated dogs with GSD-Ia, all three dogs initially maintained normal blood glucose levels. After 6–22 months, vector-treated dogs developed hypoglycemia, anorexia and lethargy, suggesting that the HDAd-cG6Pase serotype 5 vector had lost efficacy. Liver biopsies collected at this time revealed significantly elevated hepatic G6Pase activity and reduced glycogen content, when compared with affected dogs treated only by frequent feeding. Subsequently, the HDAd-cG6Pase serotype 2 vector was administered to two dogs, and hypoglycemia was reversed; however, renal dysfunction and recurrent hypoglycemia complicated their management. Administration of a serotype 2 HDAd vector prolonged survival in one GSD-Ia dog to 12 months of age and 36 months of age in the other, but the persistence of long-term complications limited HDAd vectors in the canine model for GSD-Ia.

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Acknowledgements

This project was supported by the Children's Fund for GSD Research and the Association for Glycogen Storage Disease. A debt of gratitude is extended to the members of the GSD Puppy Team, NCSU CVM-LAR staff, and NCSU CVM-CPL staff, all of whom played a vital role in the success and survival of the GSD colony. We wish to thank Mr Andrew Bird and Ms Songtao Li for excellent technical support.

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Author notes

  1. B Crane

    Present address: Current address: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA.,

  2. X Luo

    Present address: Current address: Department of Veterinary Clinical Sciences, College Veterinary Medicine, The Ohio State University, Columbus, OH, USA.,

Authors and Affiliations

  1. College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA

    B Crane, D M Kozink, T T Brown & C R Pinto

  2. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

    X Luo, A Demaster, P Zhang & D D Koeberl

  3. Department of Laboratory Animal Resources, Duke University Medical Center, Durham, NC, USA

    A Demaster, K D Williams & F Sun

  4. Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX, USA

    K Oka & L Chan

  5. Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, Scotland

    M W Jackson

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Correspondence to L Chan or D D Koeberl.

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Crane, B., Luo, X., Demaster, A. et al. Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia. Gene Ther 19, 443–452 (2012). https://doi.org/10.1038/gt.2011.86

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  • DOI: https://doi.org/10.1038/gt.2011.86

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