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Erschienen in: Journal of Inherited Metabolic Disease 6/2014

01.11.2014 | Original Article

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

verfasst von: Jean-Michel Itier, Gwénaëlle Ret, Sandra Viale, Lindsay Sweet, Dinesh Bangari, Anne Caron, Françoise Le-Gall, Bernard Bénichou, John Leonard, Jean-François Deleuze, Cécile Orsini

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 6/2014

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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.
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Metadaten
Titel
Effective clearance of GL-3 in a human iPSC-derived cardiomyocyte model of Fabry disease
verfasst von
Jean-Michel Itier
Gwénaëlle Ret
Sandra Viale
Lindsay Sweet
Dinesh Bangari
Anne Caron
Françoise Le-Gall
Bernard Bénichou
John Leonard
Jean-François Deleuze
Cécile Orsini
Publikationsdatum
01.11.2014
Verlag
Springer Netherlands
Erschienen in
Journal of Inherited Metabolic Disease / Ausgabe 6/2014
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI
https://doi.org/10.1007/s10545-014-9724-5

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