Young Mok Lee1,2, Thomas J Conlon3,4, Andrew Specht5, Kirsten E Coleman3, Laurie M Brown2, Ana M Estrella1,2, Monika Dambska2,6, Kathryn R Dahlberg6, David A Weinstein7,8,9. 1. Glycogen Storage Disease Program, Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, 06030, USA. 2. Glycogen Storage Disease Program, University of Florida College of Medicine, Gainesville, FL, USA. 3. Powell Gene Therapy Center, University of Florida, Gainesville, FL, 32610, USA. 4. CR Scientific and Compliance Consulting, LLC, Gainesville, FL, 32608, USA. 5. Department of Small Animal Clinical Sciences, University of Florida College of Veterinary Medicine, Gainesville, FL, USA. 6. Glycogen Storage Disease Program, Connecticut Children's Medical Center, Hartford, CT, USA. 7. Glycogen Storage Disease Program, Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, 06030, USA. Weinstein@uchc.edu. 8. Glycogen Storage Disease Program, University of Florida College of Medicine, Gainesville, FL, USA. Weinstein@uchc.edu. 9. Glycogen Storage Disease Program, Connecticut Children's Medical Center, Hartford, CT, USA. Weinstein@uchc.edu.
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.
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-Iadogs 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-Iadogs. 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-Iadogs 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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