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) To investigate the therapeutic potential of manipulating autophagy in GSD Ia, and 2) To investigate the reversibility of autophagy in the GSD Ia liver.
These aims may provide new treatments by repurposing approved drugs with known safety profiles. Furthermore, the interaction of drug therapy with potentially curative gene therapy 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK105434-04
Application #
9606471
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Eggerman, Thomas L
Project Start
2015-12-15
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2020-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Brooks, Elizabeth D; Kishnani, Priya S; Koeberl, Dwight D (2018) Letter to the Editors: Concerning ""Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia"" by Lee et al. J Inherit Metab Dis :
Brooks, Elizabeth D; Landau, Dustin J; Everitt, Jeffrey I et al. (2018) Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy. J Inherit Metab Dis :
Farah, Benjamin L; Landau, Dustin J; Wu, Yajun et al. (2017) Renal endoplasmic reticulum stress is coupled to impaired autophagy in a mouse model of GSD Ia. Mol Genet Metab 122:95-98
Farah, Benjamin L; Sinha, Rohit A; Wu, Yajun et al. (2017) Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa). Sci Rep 7:44408
Petta, Ioanna; Lievens, Sam; Libert, Claude et al. (2016) Modulation of Protein-Protein Interactions for the Development of Novel Therapeutics. Mol Ther 24:707-18
Landau, Dustin J; Brooks, Elizabeth Drake; Perez-Pinera, Pablo et al. (2016) In Vivo Zinc Finger Nuclease-mediated Targeted Integration of a Glucose-6-phosphatase Transgene Promotes Survival in Mice With Glycogen Storage Disease Type IA. Mol Ther 24:697-706