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...
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Springer Nature
2016-07-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606260 |
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| author | Luca Sala Zhiyi Yu Dorien Ward‐van Oostwaard Jacobus PD van Veldhoven Alessandra Moretti Karl‐Ludwig Laugwitz Christine L Mummery Adriaan P IJzerman Milena Bellin |
| author_facet | Luca Sala Zhiyi Yu Dorien Ward‐van Oostwaard Jacobus PD van Veldhoven Alessandra Moretti Karl‐Ludwig Laugwitz Christine L Mummery Adriaan P IJzerman Milena Bellin |
| author_sort | Luca Sala |
| collection | DOAJ |
| description | 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 IKr deactivation and positively shifting IKr 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. |
| format | Article |
| id | doaj-art-767b30a7cd6e491aa4968dd31eb2d71b |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-767b30a7cd6e491aa4968dd31eb2d71b2025-08-20T04:03:06ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-07-01891065108110.15252/emmm.201606260A new hERG allosteric modulator rescues genetic and drug‐induced long‐QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cellsLuca Sala0Zhiyi Yu1Dorien Ward‐van Oostwaard2Jacobus PD van Veldhoven3Alessandra Moretti4Karl‐Ludwig Laugwitz5Christine L Mummery6Adriaan P IJzerman7Milena Bellin8Department of Anatomy and Embryology, Leiden University Medical CenterGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Leiden UniversityDepartment of Anatomy and Embryology, Leiden University Medical CenterGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Leiden UniversityI. Department of Medicine (Cardiology), Klinikum rechts der Isar, Technical University of MunichI. Department of Medicine (Cardiology), Klinikum rechts der Isar, Technical University of MunichDepartment of Anatomy and Embryology, Leiden University Medical CenterGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Leiden UniversityDepartment of Anatomy and Embryology, Leiden University Medical CenterAbstract 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 IKr deactivation and positively shifting IKr 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.https://doi.org/10.15252/emmm.201606260cardiac arrhythmiadrug screeninghERGhuman induced pluripotent stem cellslong‐QT syndrome |
| spellingShingle | Luca Sala Zhiyi Yu Dorien Ward‐van Oostwaard Jacobus PD van Veldhoven Alessandra Moretti Karl‐Ludwig Laugwitz Christine L Mummery Adriaan P IJzerman Milena Bellin 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 cardiac arrhythmia drug screening hERG human induced pluripotent stem cells long‐QT syndrome |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | new herg allosteric modulator rescues genetic and drug induced long qt syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells |
| topic | cardiac arrhythmia drug screening hERG human induced pluripotent stem cells long‐QT syndrome |
| url | https://doi.org/10.15252/emmm.201606260 |
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