A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells

Sala L, Yu Z, Ward-Van Oostwaard D, Van Veldhoven JPD, Moretti A, Laugwitz KL, Mummery CL, Ijzerman AP, Bellin M (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Embo Molecular Medicine Wiley-VCH Verlag / Wiley Open Access

Book Volume: 8

Pages Range: 1065-1081

Journal Issue: 9

DOI: 10.15252/emmm.201606260

Abstract

Long-QT syndrome (LQTS) is an arrhythmogenic disorder characterised by prolongation of the QT interval in the electrocardiogram, which can lead to sudden cardiac death. Pharmacological treatments are far from optimal for congenital forms of LQTS, while the acquired form, often triggered by drugs that (sometimes inadvertently) target the cardiac hERG channel, is still a challenge in drug development because of cardiotoxicity. Current experimental models in vitro fall short in predicting proarrhythmic properties of new drugs in humans. Here, we leveraged a series of isogenically matched, diseased and genetically engineered, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients to test a novel hERG allosteric modulator for treating congenital LQTS, drug-induced LQTS or a combination of the two. By slowing IK r deactivation and positively shifting IK r inactivation, the small molecule LUF7346 effectively rescued all of these conditions, demonstrating in a human system that allosteric modulation of hERG may be useful as an approach to treat inherited and drug-induced LQTS. Furthermore, our study provides experimental support of the value of isogenic pairs of patient hiPSC-CMs as platforms for testing drug sensitivities and performing safety pharmacology.

Involved external institutions

Leiden University NL Netherlands (NL) Technische Universität München (TUM) DE Germany (DE)

How to cite

APA:

Sala, L., Yu, Z., Ward-Van Oostwaard, D., Van Veldhoven, J.P.D., Moretti, A., Laugwitz, K.-L.,... Bellin, M. (2016). A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells. Embo Molecular Medicine, 8(9), 1065-1081. https://doi.org/10.15252/emmm.201606260

MLA:

Sala, Luca, et al. "A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells." Embo Molecular Medicine 8.9 (2016): 1065-1081.

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