Sinbaglustat is efficacious in GM2 gangliosidosis primarily through inhibition of GBA2 rather than GCS

Sinbaglustat is a brain-penetrant iminosugar under clinical investigation for glycosphingolipid (GSL) storage disorders, including GM2 gangliosidosis. It inhibits non-lysosomal glucosylceramidase (GBA2) with higher potency than glucosylceramide synthase (GCS). While efficacy of related GBA2/GCS inhibitors in mouse models of Sandhoff disease was previously demonstrated, the specific contribution of GBA2 inhibition to therapeutic outcome has remained unclear. We dissected the mechanism of Sinbaglustat in Sandhoff Hexb −/− mice using 30 or 300 mg/kg/day doses, designed to preferentially inhibit GBA2 alone or both GBA2 and GCS, respectively. Sinbaglustat’s dose-dependent effects on GSLs in relation to both drug targets were consistent across enzymatic assays, patient-derived cells, and wild-type mouse brain. In Hexb −/− mice, GBA2 inhibition alone was sufficient to alter central GSL metabolism, attenuate neuroinflammatory gene expression, delay onset of motor symptoms by ≥ 2 weeks, and extend survival by 15%. High-dose treatment broadened substrate clearance via GCS inhibition and extended survival by 22%. These results reveal a therapeutic role of GBA2 inhibition in the brain and highlight sinbaglustat, an iminosugar without gastrointestinal side effects, as a promising candidate for GM2 gangliosidosis. By defining the mechanistic contribution of its dual targets, this study offers insight for dose optimization and therapeutic design in lysosomal storage disorders. Steiner and colleagues reveal that brain GBA2 inhibition by sinbaglustat drives meaningful therapeutic benefit in a murine model of GM2 gangliosidosis and that adding GCS inhibition provides additional improvement. By dissecting sinbaglustat’s dual-target actions, the study offers conceptual guidance for optimizing iminosugar therapies and advancing treatments for lysosomal storage disorders.