701. Long-Term Complications of Glycogen Storage Disease Type IA in the Dog Model Treated With Gene Replacement Therapy

Abstract

Glycogen storage disease type Ia (GSD-Ia) in dogs closely resembles human GSD-Ia where untreated patients develop complications associated with glucose-6-phosphatase (G6Pase) deficiency (hypoglycemia, hyperlipidemia, growth retardation, and early death). For the past 3 decades survival of human patients that are placed under intensive nutritional management with uncooked corn starch has improved; however, long-term complications persist including renal failure, nephrolithiasis, hepatic adenomas, and a high risk for hepatocellular carcinoma. Affected dogs fail to thrive with dietary therapy alone, but treatment with gene replacement therapy using adeno-associated viral vectors (AAV) expressing G6Pase has greatly prolonged life and prevented hypoglycemia. In this study, 7 GSD-Ia affected dogs treated with AAV-G6Pase were followed up to 8 years of life to describe long-term complications. All required readministration of AAV vector(s) pseudotyped as a new serotype to avoid anti-AAV antibodies, due to decreased ability to maintain normoglycemia during fasting. Two dogs developed chronic renal disease as denoted by polyuria, polydipsia, and azotemia at 6 and 8 years of age. Calcium oxalate and phosphate urolithiasis was detected in 2 dogs; 1 dog had evidence of polycystic ovarian disease. Four of the 7 dogs were euthanized due to reaching humane endpoints related to liver and/or kidney disease, at 3 to 8 years of life, and 1 dog succumbed to acute hypoglycemia. Necropsy revealed several focal hepatic lesions in all deceased dogs; 2 dogs had lesions confirmed histologically as hepatocellular carcinoma, the largest tumor reached 8 cm in diameter (Fig. 1). One dog demonstrated lesions consistent with hepatocellular adenoma and in the other 2, there was hepatocellular hyperplasia. There was no significant difference in amount of vector DNA in hepatic tumors compared with normal tissue (n=4 dogs), suggesting that insertional mutagenesis by the AAV vector was not the mechanism for tumor formation (Fig. 2). View Large Image | Download PowerPoint Slide View Large Image | Download PowerPoint SlideGlomerular sclerosis, fibrosis of Bowman's capsules and focal interstitial nephritis were found in the 2 dogs with clinical renal disease. Two dogs, both female, remain in good health with no evidence of liver masses appreciable on ultrasound examination; they are 4 and 5 years of age. Hepatocellular carcinoma, kidney disease, polycystic ovaries and urolithiasis are common findings among GSD-Ia patients. Here we show that the canine GSD-Ia model demonstrates similar long-term complications in spite of AAV-mediated gene replacement therapy. Further development of gene therapy is needed to prevent long-term complications of GSD-Ia.