1. Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia
- Author
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Monika Dambska, Laurie M. Brown, Young Mok Lee, Kirsten E. Coleman, Andrew Specht, Kathryn R Dahlberg, David A. Weinstein, Thomas J. Conlon, and Ana M. Estrella
- Subjects
Blood Glucose ,0301 basic medicine ,Biodistribution ,medicine.medical_specialty ,Genetic enhancement ,Genetic Vectors ,Urine ,Glycogen Storage Disease Type I ,Kidney ,Gastroenterology ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Animals ,Glycogen storage disease ,Genetics (clinical) ,business.industry ,Kidney metabolism ,Genetic Therapy ,Dependovirus ,medicine.disease ,Hypoglycemia ,Human genetics ,Europe ,Disease Models, Animal ,030104 developmental biology ,Liver ,030220 oncology & carcinogenesis ,Glucose-6-Phosphatase ,Biomarker (medicine) ,Long term safety ,business - Abstract
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. 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. 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. 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.
- Published
- 2018