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Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy.
Brooks, Elizabeth D; Landau, Dustin J; Everitt, Jeffrey I; Brown, Talmage T; Grady, Kylie M; Waskowicz, Lauren; Bass, Cameron R; D'Angelo, John; Asfaw, Yohannes G; Williams, Kyha; Kishnani, Priya S; Koeberl, Dwight D.
Afiliación
  • Brooks ED; Division of Medical Genetics, Duke University Medical Center (DUMC), Box 103856, Durham, NC, 27710, USA.
  • Landau DJ; Division of Laboratory Animal Resources, Duke University Medical Center, Durham, NC, USA.
  • Everitt JI; Division of Medical Genetics, Duke University Medical Center (DUMC), Box 103856, Durham, NC, 27710, USA.
  • Brown TT; Department of Pathology, Duke University Medical Center, Durham, NC, USA.
  • Grady KM; College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.
  • Waskowicz L; Division of Medical Genetics, Duke University Medical Center (DUMC), Box 103856, Durham, NC, 27710, USA.
  • Bass CR; Division of Medical Genetics, Duke University Medical Center (DUMC), Box 103856, Durham, NC, 27710, USA.
  • D'Angelo J; Department of Biomedical Engineering, Duke University Medical Center, Durham, NC, USA.
  • Asfaw YG; Department of Biomedical Engineering, Duke University Medical Center, Durham, NC, USA.
  • Williams K; Division of Laboratory Animal Resources, Duke University Medical Center, Durham, NC, USA.
  • Kishnani PS; Division of Laboratory Animal Resources, Duke University Medical Center, Durham, NC, USA.
  • Koeberl DD; Division of Medical Genetics, Duke University Medical Center (DUMC), Box 103856, Durham, NC, 27710, USA.
J Inherit Metab Dis ; 41(6): 965-976, 2018 11.
Article en En | MEDLINE | ID: mdl-30043186
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Terapia Genética / Enfermedad del Almacenamiento de Glucógeno Tipo I / Carcinoma Hepatocelular / Neoplasias Hepáticas Límite: Animals Idioma: En Revista: J Inherit Metab Dis Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Terapia Genética / Enfermedad del Almacenamiento de Glucógeno Tipo I / Carcinoma Hepatocelular / Neoplasias Hepáticas Límite: Animals Idioma: En Revista: J Inherit Metab Dis Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos