Effective clearance of GL‐3 in a human iPSC‐derived cardiomyocyte model of Fabry disease

Abstract

Fabry disease, a rare X-linked α-galactosidase A deficiency, causes progressive lysosomal accumulation of globotriaosylceramide (GL-3) in a variety of cell types. As the disease progresses, renal failure, left ventricular hypertrophy, and strokes may occur. Enzyme replacement therapy (ERT), with recombinant α-galactosidase A, is currently available for use to reduce GL-3 deposits. However, although it improves cardiac function and decreases left ventricular mass, GL-3 clearance upon ERT has been demonstrated in cardiac capillary endothelium but not in cardiomyocytes of patients. Relevant models are needed to understand the pathogenesis of cardiac disease and explore new therapeutic approaches. We generated induced pluripotent stem cells (iPSC) from Fabry patients and differentiated them into cardiomyocytes. In these cells, GL-3 accumulates in the lysosomes over time, resulting in phenotypic changes similar to those found in cardiac tissue from Fabry patients. Using this human in vitro model, we demonstrated that substrate reduction therapy via glucosylceramide synthase inhibition was able to prevent accumulation and to clear lysosomal GL-3 in cardiomyocytes. This new in vitro model recapitulates essential features of cardiomyocytes from patients with Fabry disease and therefore provides a useful and relevant tool for further investigations of new therapy.

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

“…The presented data confirms and significantly expands on published work demonstrating that GCS inhibitors can reduce accumulated Gb3 in cultured cells derived from Fabry patients (33,45). In particular, Itier and colleagues have shown that GCS inhibitors can reduce accumulated Gb3, suggesting a role for clearance mechanisms other than α-GalA (45).…”

“…In particular, Itier and colleagues have shown that GCS inhibitors can reduce accumulated Gb3, suggesting a role for clearance mechanisms other than α-GalA (45). Alternative molecular clearance mechanisms, which may come into play in situations of high local intracellular Gb3 levels, include removal of the α-galactose by α-N-acetylgalactosaminidase (46,47) or conversion of Gb3 to lysoGb3 by acid ceramidase (6).…”

Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease

“…However, not all disease manifestations are corrected by ERT, prompting the identification of potential adjunctive therapies. For example, although the lipids that accumulate in endothelial cells of Fabry disease are efficiently cleared by rh α-Gal A, other cell types such as the glomerular podocytes and cardiomyocytes are reportedly less responsive to enzyme therapy (9,35,36) unless treatment starts early (10). The basis for the differential responses is in part related to the biodistribution of the administered enzyme (23) and the need for early intervention.…”

“…Several lines of evidence support the notion that SRT may be effective for Fabry disease. We recently reported that treatment of induced pluripotent stem cells (iPSC)-derived cardiomyocytes from a Fabry patient with Genz-682452 prevented the accumulation of GL-3 (36). We also previously demonstrated the feasibility of this concept in Fabry mice by using an earlier generation inhibitor of GCS, Genz-112638 (18).…”

Human-induced pluripotent stem cell approaches to model inborn and acquired metabolic heart diseases

“…Recently, Itier et al derived FD iPSC-CMs from two patient with GLA mutations to understand the role of GL-3 accumulation in the pathogenesis of FD-associated cardiomyopathy (25). The FD iPSC-CMs demonstrated progressive lysosomal accumulation of GL-3, increased lysosomal storage inclusions (zebra bodies), and disorganized contractile fibers.…”