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25.05.2018 | Glycogen Storage Disease

Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia

verfasst von: Young Mok Lee, Thomas J. Conlon, Andrew Specht, Kirsten E. Coleman, Laurie M. Brown, Ana M. Estrella, Monika Dambska, Kathryn R. Dahlberg, David A. Weinstein

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 6/2018

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Abstract

Background

Viral mediated gene therapy has progressed after overcoming early failures, and gene therapy has now been approved for several conditions in Europe and the USA. Glycogen storage disease (GSD) type Ia, caused by a deficiency of glucose-6-phosphatase-α, has been viewed as an outstanding candidate for gene therapy. This follow-up report describes the long-term outcome for the naturally occurring GSD-Ia dogs treated with rAAV-GPE-hG6PC-mediated gene therapy.

Methods

A total of seven dogs were treated with rAAV-GPE-hG6PC-mediated gene therapy. The first four dogs were treated at birth, and three dogs were treated between 2 and 6 months of age to assess the efficacy and safety in animals with mature livers. Blood and urine samples, radiographic studies, histological evaluation, and biodistribution were assessed.

Results

Gene therapy improved survival in the GSD-Ia dogs. With treatment, the biochemical studies normalized for the duration of the study (up to 7 years). None of the rAAV-GPE-hG6PC-treated dogs had focal hepatic lesions or renal abnormalities. Dogs treated at birth required a second dose of rAAV after 2–4 months; gene therapy after hepatic maturation resulted in improved efficacy after a single dose.

Conclusion

rAAV-GPE-hG6PC treatment in GSD-Ia dogs was found to be safe and efficacious. GSD-Ia is an attractive target for human gene therapy since it is a monogenic disorder with limited tissue involvement. Blood glucose and lactate monitoring can be used to assess effectiveness and as a biomarker of success. GSD-Ia can also serve as a model for other hepatic monogenic disorders.

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Titel: Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia
verfasst von: Young Mok Lee
Thomas J. Conlon
Andrew Specht
Kirsten E. Coleman
Laurie M. Brown
Ana M. Estrella
Monika Dambska
Kathryn R. Dahlberg
David A. Weinstein
Publikationsdatum: 25.05.2018
Verlag: Springer Netherlands
Erschienen in: Journal of Inherited Metabolic Disease / Ausgabe 6/2018
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-018-0199-7

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Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia

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