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 I Kr deactivation and positively shifting I Kr 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 druginduced 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.

Three-dimensional cardiac microtissues composed of cardiomyocytes and endothelial cells co-differentiated from human pluripotent stem cells

“…Electrical signals for patch-clamp single cell analysis were recorded with an Axopatch 200B Amplifier (Molecular Devices) and digitized with a Digidata 1440A (Molecular Devices), and MEA experiments were performed using a 64-electrode USB-MEA system (Multichannel Systems) as previously described (Sala et al, 2016). Details are provided in the .…”

Modeling Inherited Arrhythmia Disorders Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…By maintaining a well-defined genetic background, the introduction of isogenic mutations can also improve the specificity of the quantifiable phenotypes attributable to particular mutations and potentially reveal novel relevant mechanisms of disease 104,105 . Second, the reciprocal approach is to use genome editing to correct the known mutations from patient-derived iPSC lines to create the proper controls for comparison, rather than using unrelated samples or unaffected family members 106 . This method can also provide information about the role of the genetic background or the contribution of a single mutation in complex multi-gene disorders 44 .…”

Deep Learning Based Proarrhythmia Analysis Using Field Potentials Recorded from Human Pluripotent Stem Cells Derived Cardiomyocytes

“…Moreover, the F-score results as well as other metrics confirmed the capability of the model in classification of the recordings. The introduction of combined iPSC-CMs technology and MEA system for drug discovery and cardiotoxicity assays has encouraged many scientists to test this platform and analyze its output signals [32][33][34][35][36][37] . Especially, this system is developing to a high-throughput drug screening platform, highlighting the necessity for generation of automated and sensitive analysis tools.…”