CHK1 inhibition rescues abnormal glycogen buildup in a Caenorhabditis elegans model for glycogen storage disease III

Glycogen Storage Disease Type III (GSDIII) is a rare genetic disorder caused by mutations in the AGL gene, leading to a deficiency in the glycogen debranching enzyme. This results in the accumulation of abnormal glycogen in various tissues, causing a range of symptoms, including liver enlargement and hypoglycemia. Current animal models do not fully recapitulate the severe phenotypes observed in patients, highlighting the need for improved model systems. To the best of our knowledge, this study presents the first Caenorhabditis elegans model of GSDIII, which successfully exhibits disease-relevant traits, including glycogen accumulation. Using this model, we developed a computational approach based on high-throughput screening methods, enabling the identification of key genetic modulators. Notably, we demonstrate that glycogen accumulation can be rescued by genetic and pharmacological inhibition of CHK1, a gene involved in cell cycle regulation and DNA damage response, in a variant-specific manner. These findings suggest that targeting CHK1 may represent a promising therapeutic strategy for treating GSDIII, particularly when considering specific AGL mutations. Patient-specific C. elegans model of Glycogen Storage Disease Type III shows significant glycogen accumulation. Through computational and drug screening approaches, CHK1 was identified as a potential modifier of disease-relevant phenotypes.