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

Abstract

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.

Proteomic profiling of polyglucosan bodies associated with glycogenin‐1 deficiency in skeletal muscle

“…An imbalance between glycogen synthase and branching enzyme in favour of glycogen synthase appears to promote the formation of insoluble polyglucosan [8, 11]. Inhibition of glycogen synthase ameliorates polyglucosan storage disease in different animal experimental studies, including RBCK1 deficiency, branching enzyme deficiency and Lafora disease [12–14]. Inactivation by conditional knockout of the glycogenin gene in mice results in glycogen accumulation in muscle, indicating that glycogenin is involved in the regulation of glycogen content [15].…”

Multi‐omics analysis of disulfidptosis regulators and therapeutic potential reveals glycogen synthase 1 as a disulfidptosis triggering target for triple‐negative breast cancer

“…GYS1 serves as the key rate‐limiting enzyme in glycogen synthesis, 20 and its deficiency causes muscle glycogen storage disease type 0 and death at a pathological level 21,22 . Besides, previous studies have found that targeting the GYS1 could halt the progression of epilepsy and neuroinflammation 23–25 . Additionally, numerous studies have shown that GYS1 participates in tumor growth and progression through different mechanisms such as via the nuclear factor kappa‐B (NF‐κB) pathway, the AMP‐activated protein kinase (AMPK) pathway, and the hypoxic inducible factor‐1 alpha (HIF‐1α) pathway 26–28 .…”

“… 21 , 22 Besides, previous studies have found that targeting the GYS1 could halt the progression of epilepsy and neuroinflammation. 23 , 24 , 25 Additionally, numerous studies have shown that GYS1 participates in tumor growth and progression through different mechanisms such as via the nuclear factor kappa‐B (NF‐κB) pathway, the AMP‐activated protein kinase (AMPK) pathway, and the hypoxic inducible factor‐1 alpha (HIF‐1α) pathway. 26 , 27 , 28 The enzymatic function of GYS1 can be regulated through post‐translational modification and the influence of allosteric effectors.…”