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Long-term correction of murine glycogen storage disease type Ia by recombinant adeno-associated virus-1-mediated gene transfer

Abstract

Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α), a nine-transmembrane domain, endoplasmic reticulum-associated protein expressed primarily in the liver and kidney. Previously, we showed that infusion of an adeno-associated virus (AAV) serotype 2 vector carrying murine G6Pase-α (AAV2-G6Pase-α) into neonatal GSD-Ia mice failed to sustain their life beyond weaning. We now show that neonatal infusion of GSD-Ia mice with an AAV serotype 1-G6Pase-α (AAV1-G6Pase-α) or AAV serotype 8-G6Pase-α (AAV8-G6Pase-α) results in hepatic expression of the G6Pase-α transgene and markedly improves the survival of the mice. However, only AAV1-G6Pase-α can achieve significant renal transgene expression. A more effective strategy, in which a neonatal AAV1-G6Pase-α infusion is followed by a second infusion at age one week, provides sustained expression of a complete, functional, G6Pase-α system in both the liver and kidney and corrects the metabolic abnormalities in GSD-Ia mice for the 57 week length of the study. This effective use of gene therapy to correct metabolic imbalances and disease progression in GSD-Ia mice holds promise for the future of gene therapy in humans.

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Acknowledgements

We gratefully acknowledge the University of Florida Powell Gene Therapy Center Vector Core laboratory, which produced the recombinant AAV vectors used in this study. This work was partially supported by the program project grant to BJB (#DK58327) from the National Institute of Diabetes and Digestive and Kidney Diseases.

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Correspondence to J Y Chou.

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Ghosh, A., Allamarvdasht, M., Pan, CJ. et al. Long-term correction of murine glycogen storage disease type Ia by recombinant adeno-associated virus-1-mediated gene transfer. Gene Ther 13, 321–329 (2006). https://doi.org/10.1038/sj.gt.3302650

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