Glycogen storage disease type Ia (GSD Ia) is an inherited condition characterized by deficiency of glucose-6- phosphatase (G6Pase). While dietary modification can prevent hypoglycemia in patients, current therapy fails to prevent long-term complications in many patients, including hepatic lipid accumulation associated with a high risk for hepatic adenomas that can develop into hepatocellular carcinoma. Our immediate goal is to develop new therapy for steatosis in models of GSD Ia. Based upon our preliminary studies of macroautophagy (autophagy) in GSD Ia, we seek to test our central hypothesis: Reversal of abnormalities of autophagy will reduce accumulated lipids in the GSD Ia liver. Therefore, we propose to study the hepatocellular abnormalities of GSD Ia, with the goal of developing new therapies for fatty liver by achieving the following two Specific Aims: 1) Identify the mechanism by which steatosis suppresses autophagy in GSD Ia, and 2) Evaluate genome editing to prevent long-term complications of GSD Ia.
These aims may provide new treatments by repurposing approved drugs with known safety profiles. Furthermore, the interaction of drug therapy with potentially curative genome editing will be investigated, with the goal of permanently reversing the hepatocellular abnormalities of GSD Ia. If successful in GSD Ia, developing therapies that reduce hepatic lipid accumulations also could be effective at reversing steatosis in other conditions, including metabolic liver diseases and non-alcoholic fatty liver disease.
Improved therapy for GSD Ia will advance the treatment of a rare, orphan disease, representing an unmet medical need. Furthermore, new drug therapy to reduce hepatosteatosis in GSD Ia could potentially provide therapy for non-alcoholic fatty liver disease.
