Small molecule inhibition of glycogen storage as therapy for glycogenoses Glycogen is a normal branched polymer of glucose that acts as a reserve of glucose units, to be used for anabolism or as a source of energy. Abnormal glycogen metabolism is associated with some generalized metabolic disorders, most notably type 2 diabetes and insulin resistance, but in addition a number of individual genetic glycogen storage diseases (GSDs) or glycogenoses have been identified. In these, mutations in genes impacting glycogen metabolism result in abnormal glycogen deposits in a variety of tissues, often with serious and even fatal consequences. No truly effective treatments are available for the most serious disorders. Genetic depletion of glycogen levels has recently been shown to have efficacy in alleviating the pathology in a mouse model of Pompe disease. The main premise for this proposal is that suppression of glycogen accumulation is a promising therapeutic approach to combat glycogenoses in general and Pompe disease in particular.
Aim 1 : Identification of small molecule inhibitors of glycogen synthase. We will search for active site and allosteric site inhibitors of glycogen synthase by high-throughput screens using novel assays. Lead compounds will form the basis to develop focused libraries of chemically related molecules to enhance both potency and biological efficacy. Positives from the above screens will be confirmed by more extensive enzyme kinetic study and promising candidates evaluated in model cell systems and then at the whole animal level (see Aims 2 and 3).
Aim 2 : Cell-based analyses of effectors of glycogen accumulation. We have developed a novel ELISA assay to monitor cellular glycogen accumulation based on detection of glycogen by interaction with a GST fusion-protein containing a carbohydrate binding module (CBM) from a known glycogen binding protein, Stbd1. The assay will be applied to evaluate and validate any candidate glycogen synthase inhibitors identified in Aim 1 as well as screening of compound libraries to identify novel inhibitors.
Aim 3 : Testing inhibitors of glycogen accumulation in mouse models of Pompe disease. Compounds identified in Aims 1 and 2 that show most promise will be tested in mice for toxicology and pharmacokinetics. Suitable compounds will then be administered to Pompe mice to assess their effects on glycogen overaccumulation, cardiac hypertrophy and locomotor impairment associated with the disease. In the future, we test compounds with other mouse models of glycogenoses. Even one new effective drug would be of major importance for Pompe patients and possibly patients with other glycogen storage diseases.

Public Health Relevance

Glycogen is a normal storage form of glucose in tissues but abnormal glycogen stores cause several diseases, including Pompe disease which, in its most severe form, causes death within the first year of life. Experiments with a mouse model of Pompe disease have shown that reducing glycogen alleviates disease symptoms. This proposal seeks to identify small molecule compounds that suppress glycogen accumulation and hence may be developed into drugs to treat Pompe disease and other related diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
High Priority, Short Term Project Award (R56)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Laughlin, Maren R
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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