title: 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.
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.
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Luca
authors.identifier: 0000-0002-4129-6632
authors.initials: L
authors.lastname: Sala
authors.affiliation: Gorlaeus Laboratories, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Dorien
authors.initials: D
authors.lastname: Ward-van Oostwaard
authors.affiliation: Gorlaeus Laboratories, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Jacobus Pd
authors.initials: JP
authors.lastname: van Veldhoven
authors.affiliation: I. Department of Medicine (Cardiology), Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Moretti
authors.affiliation: I. Department of Medicine (Cardiology), Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Karl-Ludwig
authors.initials: KL
authors.lastname: Laugwitz
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
authors.affiliation: Gorlaeus Laboratories, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands m.bellin@lumc.nl.
authors.forename: Milena
authors.identifier: 0000-0001-5380-6743
authors.initials: M
authors.lastname: Bellin
mesh_terms: D002317:Cardiovascular Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D000072237:ERG1 Potassium Channel / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000502:physiology*; D008133:Long QT Syndrome / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology*
chemical_list: D002317:Cardiovascular Agents; D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human
keywords: cardiac arrhythmia; drug screening; hERG; human induced pluripotent stem cells; long‐QT syndrome