Pharmacological approaches for treating glycogen storage disorders involving polyglucosan body accumulation

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.

KEYWORDS:

• Glycogen storage disorders
• glycogen
• polyglucosan
• polyglucosan bodies
• image-based high throughput screening

Article Highlights

• Glycogen storage disorders (GSDs) involving accumulation of polyglucosan bodies (PB) are devastating disorders affecting the nervous system, muscle and liver.

• All well-established 15 GSDs are caused by defects in carbohydrate interacting-enzymes. Since these enzymes contain defined functional modules, all GSDs should be amenable to therapy mediated by small-molecules interacting with these functional modules.

• Careful design of small mild molecular inhibitors which target several enzymes with the same function, yet preserving their house keeping activity, is a promising pharmacological approach for treating PB-GSDs.

• Mild and specific glycogen synthase inhibitors constitute a promising pharmacological avenue for treating PB-GSDs.

• The unique protein composition of the PB inclusion bodies, differentiating them from other inclusion bodies, can serve as a target for their elimination.

• Image-based high throughput screening campaigns for identifying PB and other cellular features can potentially serve as a practical tool for the discovery of PB-clearing drug candidates with minimal effect on other cellular features.

This box summarizes key points contained in the article.

Declaration of Interest

Or Kakhlon has received support in the form of grants from Kamin (Israeli Ministry of Economics), Israel Ministry of Science and technology, APBD Research Foundation, and Association Francaise contre les Myopathies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

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Funding

This paper was not funded