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

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 I K r deactivation and positively shifting I K 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. Synopsis Congenital and drug‐induced long‐QT syndrome (LQTS) can be rescued in vitro by a new hERG allosteric activator. Isogenic pairs of human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) prove to be a reliable tool for drug screening and safety pharmacology. The small molecule LUF7346 is a potent and selective type‐1 hERG activator. Congenital LQTS, drug‐induced LQTS and a combination of the two were rescued by hERG activation. Electrophysiological phenotype differences exist among CMs derived from different control lines. Isogenic pairs of hPSC‐CMs represent a valuable tool for drug screening and safety pharmacology. Graphical Abstract Congenital and drug‐induced long‐QT syndrome (LQTS) can be rescued in vitro by a new hERG allosteric activator. Isogenic pairs of human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) prove to be a reliable tool for drug screening and safety pharmacology.