Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy.
J Inherit Metab Dis
; 41(6): 965-976, 2018 11.
Article
in En
| MEDLINE
| ID: mdl-30043186
ABSTRACT
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.
Full text:
1
Database:
MEDLINE
Main subject:
Genetic Therapy
/
Glycogen Storage Disease Type I
/
Carcinoma, Hepatocellular
/
Liver Neoplasms
Limits:
Animals
Language:
En
Journal:
J Inherit Metab Dis
Year:
2018
Type:
Article
Affiliation country:
United States