Lucerastat

Lucerastat, the galactose form of Miglustat, is an orally-available inhibitor of glucosylceramide synthase (GCS). Lucerastat has the potential for Fabry disease study[1][2].

Signaling Pathways >> Others >> Others

Research Areas >> Metabolic Disease

Fabry patient-derived fibroblasts with the genotypes R301G (residual -GalA activity; 20%) R220X (<3%) and W162X (<1%). Cell Viability Assay[2]. Cell Line: Fabry patient-derived fibroblasts with the genotypes R301G (residual -GalA activity; 20%) R220X (<3%) and W162X (<1%). Concentration: Incubation Time: 9 days. Result: Dose-dependently inhibited GCS, reducing glucosylceramide and increasing sphingomyelin.

Lucerastat (1200 mg/kg/day food admix), a GCS inhibitor, reduces Gb3 in the absence of residual -GalA activity[2]. Animal Model: Fabry mice (Gla-/0 and Gla-/-, n = 5 or 6 for each gender)[2]. Dosage: 1200 mg/kg/day food admix. Administration: Food admix for 20 weeks. Result: Reduced lipid storage in two major organs affected by FD: mean Gb3 in the kidneys (-33%, p<0.01). and α-galactose- terminated glycosphingolipids in the dorsal root ganglia (-48%, p<0.05). In the liver of the Fabry mice, mean glucosylceramide (GlcCer (24:0)) was reduced (-59%, p<0.001) in addition to Gb3 (24:1) (-37%, p<0.05) demonstrating substrate reduction through GCS inhibition.

[1]. Sanne J van der Veen, et al. Developments in the Treatment of Fabry Disease. J Inherit Metab Dis. 2020 Feb 21.

[2]. R.W.D. Welford, et al. Lucerastat, an Iminosugar for Substrate Reduction Therapy in Fabry Disease: Preclinical Evidence.