Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation.

backgroundSteroid 5 alpha-reductase 3-related congenital disorder of glycosylation (SRD5A3-CDG) is a rare inherited disease characterized by neurological dysfunction, including ataxia, as well as developmental and visual impairments, with no approved treatments. The disease is caused by defects in dolichol biosynthesis, a pathway essential for protein glycosylation. However, the lack of suitable in vivo models has limited both mechanistic insight and therapeutic development.

methodsWe generated a Caenorhabditis elegans model carrying a patient-relevant loss-of-function mutation and performed a motility-based phenotypic drug repurposing screen to identify compounds that improve disease-relevant phenotypes. Lead compounds were evaluated in behavioral, neuronal, and metabolomic assays in worms and in fibroblasts from four individuals with SRD5A3-CDG.

resultsHere we show that SRD5A3-deficient worms exhibit developmental delay, neuronal dysfunction, and metabolic alterations consistent with dysregulation of the mevalonate pathway. The screen identifies multiple classes of compounds that improve motility, including the cholesterol-lowering drug atorvastatin. Atorvastatin improves multiple disease-relevant phenotypes in the worm model. In patient-derived fibroblasts, treatment partially restores the balance between polyprenol and dolichol, which is disrupted in SRD5A3-CDG.

conclusionsThese findings establish an in vivo model of SRD5A3-CDG and identify modulation of the mevalonate pathway as a potential therapeutic strategy. The results support further investigation of atorvastatin as a repurposed treatment and demonstrate an approach for combining model organism screening with human cell validation to accelerate rare disease drug discovery.