Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy
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Glycogen storage disease type Ia (GSD Ia) in dogs closely resembles human GSD Ia. Untreated patients with GSD Ia develop complications associated with glucose-6-phosphatase (G6Pase) deficiency. Survival of human patients on intensive nutritional management has improved; however, long-term complications persist including renal failure, nephrolithiasis, hepatocellular adenomas (HCA), and a high risk for hepatocellular carcinoma (HCC). Affected dogs fail to thrive with dietary therapy alone. Treatment with gene replacement therapy using adeno-associated viral vectors (AAV) expressing G6Pase has greatly prolonged life and prevented hypoglycemia in affected dogs. However, long-term complications have not been described to date.
Five GSD Ia-affected dogs treated with AAV-G6Pase were evaluated. Dogs were euthanized due to reaching humane endpoints related to liver and/or kidney involvement, at 4 to 8 years of life. Necropsies were performed and tissues were analyzed.
Four dogs had liver tumors consistent with HCA and HCC. Three dogs developed renal failure, but all dogs exhibited progressive kidney disease histologically. Urolithiasis was detected in two dogs; uroliths were composed of calcium oxalate and calcium phosphate. One affected and one carrier dog had polycystic ovarian disease. Bone mineral density was not significantly affected.
Here, we show that the canine GSD Ia model demonstrates similar long-term complications as GSD Ia patients in spite of gene replacement therapy. Further development of gene therapy is needed to develop a more effective treatment to prevent long-term complications of GSD Ia.
We would like to acknowledge inspiration and support from Dr. Emory and Mrs. Mary Chapman and their son Christopher, and from Dr. John and Mrs. Michelle Kelly. We appreciate the care that these dogs received from the Duke Division of Laboratory Animal Resources staff, namely Ms. Laura Jordan and the veterinary support from Drs. Francis Sun, Amanda DeMaster, Sarah Faircloth, Shannon Smith, Feli Smith, Angela Garner, and Jai Tubbs, and veterinary technicians, namely Christian Marsini, Kelly Franke, Diego Zapata, and Jeff Lee. The collective support from the multiple students and staff in the dog feeding team over these years ensured a long, comfortable life for the GSD Ia dogs.
This work received funding provided by the Children’s Fund for GSD Research, Children’s Miracle Network, Association for Glycogen Storage Disease, For the Love of Christopher, and the Alice and YT Chen Center for Pediatric Genetics and Genomics, and grant R01DK105434-01A1 from the National Institute of Diabetes and Digestive and Kidney Diseases.
Compliance with ethical standards
Conflict of interest
E. D. Brooks, D. J. Landau, J. I. Everitt, T. T. Brown, K. M. Grady, L. Waskowicz, C. R. Bass, J. D’Angelo, Y. G. Asfaw, K. Williams, P. Kishnani, and D. D. Koeberl declare that they have no conflict of interest.
All institutional and national guidelines for the care and use of laboratory animals were followed.
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