LAUSR

ABSTRACT Introduction: Glycogen storage disorders (GSDs) are mainly caused by over-accumulation of normal or malconstructed glycogen. A few GSDs, Adult Polyglucosan Body Disease (APBD), Andersen Disease, Tarui Disease and Lafora Disease are also associated with pathogenic inclusion bodies called polyglucosan bodies (PB) consisting of malconstructed glycogen (polyglucosan) in complex with several enzymes of glycogen metabolism. A treatment for GSDs is urgently required. This review examines the pharmacological avenue for curing PB-involving GSDs. Areas covered: I describe here the pros and cons of the structure-based drug development approach. This functional module-based approach can generate efficacious drugs, but with a large pleiotropic potential. Solutions based on modulations of affinity and specificity of putative drugs and on multi-targeting are then described. Next I discuss the targets of GSD pharmacological therapy: glycogen synthase (GYS), glycogen metabolizing enzymes and inclusion bodies. Finally, image-based high-throughput screening (HTS) is described as a methodological platform for PB-involving GSD drug discovery. Expert opinion: The conclusion of this review is that the pharmacological approach should be the leading therapeutic strategy for curing PB-involving GSDs. This approach enables broad characterization of underlying causes of PB-involving GSDs, an exhaustive examination of multiple mechanistic strategies for therapy and fast translational potential.