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Therapeutic effects of lomerizine on vasculopathy in Fabry disease
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Therapeutic effects of lomerizine on vasculopathy in Fabry disease
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Journal Article
Therapeutic effects of lomerizine on vasculopathy in Fabry disease
2025
Overview
Fabry disease (FD) is a lysosomal storage disorder in which α-galactosidase (GLA) deficiency leads to a build-up of globo-triaosylceramide (Gb3) in various cell types. Gb3 accumulation leads to the abnormalities of microvascular function associated with FD. Previously, we discovered significant abnormalities in vascular endothelial cells (VECs) derived from FD-induced pluripotent stem cells. We then used a cell-based system to screen a group of clinical compounds for candidates capable of rescuing those abnormalities. Lomerizine was one of the most promising candidates because it alleviated a variety of FD-associated phenotypes both in vitro and in vivo. Lomerizine reduced mitochondria Ca
2+
levels, ROS generation, and the maximal respiration of FD-VECs in vitro. This led to a suppression of the endothelial-to-mesenchymal transition (EndMT) and rescued FD-VEC function. Furthermore, FD-model mice (Gla−/−/TSP1Tg) treated orally with lomerizine for 6 months showed clear improvement of several FD phenotypes, including left ventricular hypertrophy, renal fibrosis, anhidrosis, and heat intolerance. Thus, our results suggest lomerizine as a novel candidate for FD therapy.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ alpha-Galactosidase - genetics
/ alpha-Galactosidase - metabolism
/ Animals
/ Endothelial Cells - drug effects
/ Endothelial Cells - metabolism
/ Enzymes
/ Fabry Disease - complications
/ Fabry Disease - drug therapy
/ Fibrosis
/ Heart
/ Humanities and Social Sciences
/ Humans
/ iPSCs
/ Kinases
/ Male
/ Mice
/ Piperazines - therapeutic use
/ Reactive Oxygen Species - metabolism
/ Science
