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Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors

Gene Therapy volume 9, pages 1015–1022 (2002)Cite this article

Abstract

Therapy in glycogen storage disease type Ia (GSD Ia), an inherited disorder of carbohydrate metabolism, relies on nutritional support that postpones but fails to prevent long-term complications of GSD Ia. In the canine model for GSD Ia, we evaluated the potential of intravenously delivered adeno-associated virus (AAV) vectors for gene therapy. In three affected canines, liver glycogen was reduced following hepatic expression of canine glucose-6-phosphatase (G6Pase). Two months after AAV vector administration, one affected dog had normalization of fasting glucose, cholesterol, triglycerides, and lactic acid. Concatamerized AAV vector DNA was confirmed by Southern blot analysis of liver DNA isolated from treated dogs, as head-to-tail, head-to-head, and tail-to-tail concatamers. Six weeks after vector administration, the level of vector DNA signal in each dog varied from one to five copies per cell, consistent with variation in the efficiency of transduction within the liver. AAV vector administration in the canine model for GSD Ia resulted in sustained G6Pase expression and improvement in liver histology and in biochemical parameters.

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Acknowledgements

We thank Ibrahim Bori, Eric Faulkner, Kathy Frid, Kwang Ok Shin and Joe Zeidner for excellent technical support, and Andrea Amalfitano and Dieksha Bali for insightful comments. We are very grateful to Dr Steve Van Camp for his contributions to the establishment of the canine GSD Ia colony. This work was supported a Howard Hughes Young Investigator Award (DDK), and by the Association for Glycogen Storage Disease.

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Authors and Affiliations

  1. Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA

    RM Beaty, D Peterson, A Bird, P Kishnani, A Boney, YT Chen & DD Koeberl

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

    M Jackson, T Brown & T Juopperi

  3. Division of Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

    DK Benjamin Jr

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Beaty, R., Jackson, M., Peterson, D. et al. Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors. Gene Ther 9, 1015–1022 (2002). https://doi.org/10.1038/sj.gt.3301728

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