Efficacy of Ryr2 Inhibitor EL20 in Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with Catecholaminergic Polymorphic Ventricular Tachycardia.

Authors

Tarah A. Word, Baylor College of MedicineFollow
Ann P. Quick, Baylor College of Medicine
Christina Y. Miyake, Baylor College of Medicine
Mayra K. Shak, Baylor College of Medicine
Xiaolu Pan, Baylor College of Medicine
Jean J. Kim, Baylor College of Medicine
Hugh D. Allen, Baylor College of Medicine
Martha Sibrian-Vazquez, Elex Biotech Inc, Portland, OR, USA.Follow
Robert M. Strongin, Portland State UniversityFollow
Andrew P. Landstrom, Duke University School of Medicine
Xander H T Wehrens, Baylor College of Medicine

Published In

Journal of Cellular and Molecular Medicine

Document Type

Article

Publication Date

6-10-2021

Subjects

Stem Cells -- Research, Cardiology

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal-dominant variants in the cardiac ryanodine receptor type-2 (RYR2) gene. Mutations in RYR2 promote calcium (Ca ) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias. Recently, it was demonstrated that tetracaine derivative EL20 specifically inhibits mutant RyR2, normalizes Ca handling and suppresses arrhythmias in a CPVT mouse model. The objective of this study was to determine whether EL20 normalizes SR Ca handling and arrhythmic events in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a CPVT patient. Blood samples from a child carrying RyR2 variant RyR2 variant Arg-176-Glu (R176Q) and a mutation-negative relative were reprogrammed into iPSCs using a Sendai virus system. iPSC-CMs were derived using the Stemdiff kit. Confocal Ca imaging was used to quantify RyR2 activity in the absence and presence of EL20. iPSC-CMs harbouring the R176Q variant demonstrated spontaneous SR Ca release events, whereas administration of EL20 diminished these abnormal events at low nanomolar concentrations (IC = 82 nM). Importantly, treatment with EL20 did not have any adverse effects on systolic Ca handling in control iPSC-CMs. Our results show for the first time that tetracaine derivative EL20 normalized SR Ca handling and suppresses arrhythmogenic activity in iPSC-CMs derived from a CPVT patient. Hence, this study confirms that this RyR2-inhibitor represents a promising therapeutic candidate for treatment of CPVT.

Rights

Copyright (c) 2021 The Authors

This work is licensed under a Creative Commons Attribution 4.0 International License.

Locate the Document

https://doi.org/10.1111/jcmm.16521

DOI

10.1111/jcmm.16521

Persistent Identifier

https://archives.pdx.edu/ds/psu/35954

Citation Details

Word, T. A., Quick, A. P., Miyake, C. Y., Shak, M. K., Pan, X., Kim, J. J., Allen, H. D., Sibrian‐Vazquez, M., Strongin, R. M., Landstrom, A. P., & Wehrens, X. H. T. (2021). Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell‐derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia. Journal of Cellular and Molecular Medicine, jcmm.16521. https://doi.org/10.1111/jcmm.16521