Open AccessA new hERG allosteric modulator rescues genetic and drug‐induced long‐ QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells
Author(s) -
Sala Luca,
Yu Zhiyi,
Wardvan Oostwaard Dorien,
Veldhoven Jacobus PD,
Moretti Alessandra,
Laugwitz KarlLudwig,
Mummery Christine L,
IJzerman Adriaan P,
Bellin Milena
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606260
Subject(s) - herg , induced pluripotent stem cell , allosteric regulation , long qt syndrome , cardiotoxicity , pharmacology , drug , allosteric modulator , drug discovery , qt interval , phenotype , medicine , biology , bioinformatics , potassium channel , genetics , receptor , embryonic stem cell , toxicity , gene
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 (hi PSC ‐ CM s) from patients to test a novel hERG allosteric modulator for treating congenital LQTS , drug‐induced LQTS or a combination of the two. By slowing I K r deactivation and positively shifting I K r inactivation, the small molecule LUF 7346 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 hi PSC ‐ CM s as platforms for testing drug sensitivities and performing safety pharmacology.