Neurological glycogen storage diseases and emerging therapeutics.

Glycogen storage diseases (GSDs) comprise a group of inherited metabolic disorders characterized by defects in glycogen metabolism, leading to abnormal glycogen accumulation in multiple tissues, most notably affecting the liver, skeletal muscle, and heart. Recent findings have uncovered the importance of glycogen metabolism in the brain, sustaining a myriad of physiological functions and linking its perturbation to central nervous system (CNS) pathology. This link resulted in classification of neurological-GSDs (n-GSDs), a group of diseases with shared deficits in neurological glycogen metabolism. The n-GSD patients exhibit a spectrum of clinical presentations with common etiology while requiring tailored therapeutic approaches from the traditional GSDs. Recent research has elucidated the genetic and biochemical mechanisms and pathophysiological basis underlying different n-GSDs. Further, the last decade has witnessed some promising developments in novel therapeutic approaches, including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), small molecule drugs, and gene therapy targeting key aspects of glycogen metabolism in specific n-GSDs. This preclinical progress has generated noticeable success in potentially modifying disease course and improving clinical outcomes in patients. Herein, we provide an overview of current perspectives on n-GSDs, emphasizing recent advances in understanding their molecular basis, therapeutic developments, underscore key challenges and the need to deepen our understanding of n-GSDs pathogenesis to develop better therapeutic strategies that could offer improved treatment and sustainable benefits to the patients.

Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model.

Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules that aggregate into Lafora bodies. Lafora bodies are particularly damaging in the brain, where the aggregation drives seizures with increasing severity and frequency, coupled with neurodegeneration. Previous work employed mouse genetic models to reduce glycogen synthesis by approximately 50%, and this strategy significantly reduced Lafora body formation and disease phenotypes. Therefore, an antisense oligonucleotide (ASO) was developed to reduce glycogen synthesis in the brain by targeting glycogen synthase 1 (Gys1). To test the distribution and efficacy of this drug, the Gys1-ASO was administered to Epm2b-/- mice via intracerebroventricular administration at 4, 7, and 10 months. The mice were then sacrificed at 13 months and their brains analyzed for Gys1 expression, glycogen aggregation, and neuronal excitability. The mice treated with Gys1-ASO exhibited decreased Gys1 protein levels, decreased glycogen aggregation, and reduced epileptiform discharges compared to untreated Epm2b-/- mice. This work provides proof of concept that a Gys1-ASO halts disease progression of EPM2B mutations of Lafora disease.