Using Stem Cell Derived Cardiomyocytes for Safety Assessment of Pharmaceutical Compounds

Y Abassi. ACEA Biosciences, Cell Biology, USA

The vast majority of the drugs withdrawn from the market due to association with Torsades de Pointes (TdP) arrhythmia appear to interfere with the Ikr repolarization current mediated through the hERG potassium channel. Consequently, the ICH S7B guidelines recommend that all new chemical entities should be subjected to hERG repolarization assay, typically using cell lines that recombinantly express hERG protein. However, in the last decade it has become evident that not all hERG channel inhibitors result in TdP and not all compounds that induce QT prolongation and TdP necessarily inhibit hERG. In order to better understand and assess the different kinds of drug liabilities associated with hERG channel inhibition and modulation we have used a panel of drugs and compounds which (i) directly bind and inhibit hERG channel function (overt inhibitors); (ii) compounds which inhibit hERG as well as other channels and therefore compensate for the Ikr block (covert inhibitors) and (iii) compounds which interfere with the trafficking of hERG channel protein to the plasma membrane (trafficking inhibitors). We have assessed the activity of these compounds using human induced pluripotent stems cell-derived cardiomyocytes (iCells) together with a system which utilizes impedance measurement to record the beating activity of the spontaneously beating cardiomyocytes (Abassi et al. (2012) BJP, 165, 1424-1441). Using analysis parameters such as beating rate (BR) and irregularity of BR (BRI), our data clearly shows that overt hERG channel inhibitors disrupt the periodicity of beating of iCell cardiomyocytes leading to plateau oscillations and a signature waveform that is typical of these class of compounds. Covert hERG channel inhibitors at physiologic concentrations do not appear to affect cardiac function and therefore appear to be safe. hERG trafficking inhibitors display a time-dependent effect on the periodicity of beating that manifests several hours after compound dosing. In summary, the results clearly show that dynamic monitoring of stem cell derived cardiomyocyte beating can be used in a predictive way to assess various types of hERG channel modulators and provide additional information to electrophysiological methods.