Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene coding for α-
galactosidase A (α-GalA). The deleterious mutations lead to accumulation of α-GalA substrates, including
globotriaosylceramide (Gb3) and globotriaosylsphingosine. Progressive
glycolipid storage results in cellular dysfunction, leading to organ damage and clinical disease, i.e.
neuropathic pain, impaired renal function and
cardiomyopathy. Many Fabry patients are treated by bi-weekly
intravenous infusions of replacement
enzyme. While the only available oral
therapy is an α-GalA chaperone, which is indicated for a limited number of patients with specific 'amenable' mutations.
Lucerastat is an orally bioavailable inhibitor of
glucosylceramide synthase (GCS) that is in late stage clinical development for
Fabry disease. Here we investigated the ability of
lucerastat to lower Gb3, globotriaosylsphingosine and lysosomal staining in cultured fibroblasts from 15 different Fabry patients. Patients' cells included 13 different pathogenic variants, with 13 cell lines harboring GLA mutations associated with the classic disease phenotype.
Lucerastat dose dependently reduced Gb3 in all cell lines. For 13 cell lines the Gb3 data could be fit to an IC50 curve, giving a median IC50 [interquartile range (IQR)] = 11 μM (8.2-18); the median percent reduction (IQR) in Gb3 was 77% (70-83).
Lucerastat treatment also dose dependently reduced
LysoTracker Red staining of acidic compartments.
Lucerastat's effects in the cell lines were compared to those with current treatments-
agalsidase alfa and
migalastat. Consequently, the GCS inhibitor
lucerastat provides a viable mechanism to reduce Gb3 accumulation and lysosome volume, suitable for all Fabry patients regardless of genotype.