Cellular models developed to better predict proarrhythmic liability of drug candidates include commercially-available human stem cell-derived cardiomyocytes (hiPSC-CM) obtained from healthy subjects. Cardiac safety assessment, however, should not be limited to preclinical models using “healthy” cellular systems. It is relevant to test drugs in systems recapitulating various cardiac conditions found in the general population. Similarly, modeling diseases in hiPSC-CM can be used for the discovery of novel therapies. Generating hiPSC-CM from patients is a challenging, costly and lengthy process not suitable for effective drug testing. Thus, alternative approaches are needed.
Developing an assay using hiPSC-CM to model mutation-specific arrhythmogenic diseases to screen drug candidates represents a real opportunity at a time where personalized medicine is the focus of many drug safety/ discovery programs. Long QT type 2 (hERG channel mutation) is a familial arrhythmogenic syndrome characterized by delayed repolarization, a prolonged QT interval in the electrocardiogram and a life-threatening polymorphic ventricular tachycardia known as torsades de pointe (TdP)1. Drug response can be altered in conditions where repolarization is compromised.
The objective of this study is to recapitulate the cellular phenotype of a long QT syndrome type 2 by overexpressing a dominant negative hERG mutation (G628S)2 in hiPSC-CM (Cor.4U™). We show that unlike non-transfected cells, G628S cells become arrhythmogenic in the presence of specific hERGblockade (dofetilide).