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Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia.

Publication ,  Journal Article
Word, TA; Quick, AP; Miyake, CY; Shak, MK; Pan, X; Kim, JJ; Allen, HD; Sibrian-Vazquez, M; Strongin, RM; Landstrom, AP; Wehrens, XHT
Published in: J Cell Mol Med
June 10, 2021

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 (Ca2+ ) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias. Recently, it was demonstrated that tetracaine derivative EL20 specifically inhibits mutant RyR2, normalizes Ca2+ handling and suppresses arrhythmias in a CPVT mouse model. The objective of this study was to determine whether EL20 normalizes SR Ca2+ 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 StemdiffTM kit. Confocal Ca2+ imaging was used to quantify RyR2 activity in the absence and presence of EL20. iPSC-CMs harbouring the R176Q variant demonstrated spontaneous SR Ca2+ release events, whereas administration of EL20 diminished these abnormal events at low nanomolar concentrations (IC50  = 82 nM). Importantly, treatment with EL20 did not have any adverse effects on systolic Ca2+ handling in control iPSC-CMs. Our results show for the first time that tetracaine derivative EL20 normalized SR Ca2+ 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.

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Published In

J Cell Mol Med

DOI

EISSN

1582-4934

Publication Date

June 10, 2021

Volume

25

Issue

13

Start / End Page

6115 / 6124

Location

England

Related Subject Headings

  • Biochemistry & Molecular Biology
  • 3404 Medicinal and biomolecular chemistry
  • 3101 Biochemistry and cell biology
  • 1103 Clinical Sciences
  • 0601 Biochemistry and Cell Biology
  • 0304 Medicinal and Biomolecular Chemistry
 

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Word, T. A., Quick, A. P., Miyake, C. Y., Shak, M. K., Pan, X., Kim, J. J., … 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. J Cell Mol Med, 25(13), 6115–6124. https://doi.org/10.1111/jcmm.16521
Word, Tarah A., Ann P. Quick, Christina Y. Miyake, Mayra K. Shak, Xiaolu Pan, Jean J. Kim, Hugh D. Allen, et al. “Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia.J Cell Mol Med 25, no. 13 (June 10, 2021): 6115–24. https://doi.org/10.1111/jcmm.16521.
Word, Tarah A., et al. “Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia.J Cell Mol Med, vol. 25, no. 13, June 2021, pp. 6115–24. Pubmed, doi:10.1111/jcmm.16521.
Word TA, Quick AP, Miyake CY, Shak MK, Pan X, Kim JJ, Allen HD, Sibrian-Vazquez M, Strongin RM, Landstrom AP, Wehrens XHT. Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia. J Cell Mol Med. 2021 Jun 10;25(13):6115–6124.
Journal cover image

Published In

J Cell Mol Med

DOI

EISSN

1582-4934

Publication Date

June 10, 2021

Volume

25

Issue

13

Start / End Page

6115 / 6124

Location

England

Related Subject Headings

  • Biochemistry & Molecular Biology
  • 3404 Medicinal and biomolecular chemistry
  • 3101 Biochemistry and cell biology
  • 1103 Clinical Sciences
  • 0601 Biochemistry and Cell Biology
  • 0304 Medicinal and Biomolecular Chemistry