Pluripotent Stem Cell-Based Drug Screening Reveals Cardiac Glycosides as Modulators of Myotonic Dystrophy Type 1

Yves Maury; Pauline Poydenot; Benjamin Brinon; Lea Lesueur; Jacqueline Gide; Sylvain Roquevière; Julien Côme; Hélène Polvèche; Didier Auboeuf; Jérome Alexandre Denis; Geneviève Pietu; Denis Furling; Marc Lechuga; Sandrine Baghdoyan; Marc Peschanski; Cécile Martinat

doi:10.1016/j.isci.2018.12.019

Pluripotent Stem Cell-Based Drug Screening Reveals Cardiac Glycosides as Modulators of Myotonic Dystrophy Type 1

iScience. 2019 Jan 25:11:258-271. doi: 10.1016/j.isci.2018.12.019. Epub 2018 Dec 27.

Authors

Yves Maury¹, Pauline Poydenot¹, Benjamin Brinon¹, Lea Lesueur², Jacqueline Gide¹, Sylvain Roquevière², Julien Côme¹, Hélène Polvèche³, Didier Auboeuf³, Jérome Alexandre Denis², Geneviève Pietu², Denis Furling⁴, Marc Lechuga¹, Sandrine Baghdoyan², Marc Peschanski⁵, Cécile Martinat⁶

Affiliations

¹ CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France.
² INSERM, UMR 861, UEVE, ISTEM, AFM, 91100 Corbeil-Essonnes, France.
³ LBMC, 69007 Lyon, France.
⁴ Sorbonne Universités UPMC Univ Paris 06, INSERM, Centre de Recherche en Myologie - UMRS974, Institut de Myologie, 75013 Paris, France.
⁵ CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France; INSERM, UMR 861, UEVE, ISTEM, AFM, 91100 Corbeil-Essonnes, France.
⁶ INSERM, UMR 861, UEVE, ISTEM, AFM, 91100 Corbeil-Essonnes, France. Electronic address: cmartinat@istem.fr.

Abstract

There is currently no treatment for myotonic dystrophy type 1 (DM1), the most frequent myopathy of genetic origin. This progressive neuromuscular disease is caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors, resulting in alternative splicing misregulation. By combining human mutated pluripotent stem cells and phenotypic drug screening, we revealed that cardiac glycosides act as modulators for both upstream nuclear aggregations of DMPK mRNAs and several downstream alternative mRNA splicing defects. However, these occurred at different drug concentration ranges. Similar biological effects were recorded in a DM1 mouse model. At the mechanistic level, we demonstrated that this effect was calcium dependent and was synergic with inhibition of the ERK pathway. These results further underscore the value of stem-cell-based assays for drug discovery in monogenic diseases.

Keywords: Cell Biology; Molecular Biology; Physiology.