Comprehensive Cardiac Safety Screening: Pharmacology of Stem Cell-Derived Cardiomyocytes using High-Throughput Automated Patch Clamp

Abstract

Drug discovery is challenged by poor predictability of proarrhythmic effects of present safety screening approaches. The Comprehensive in Vitro Proarrhythmia Assay (CiPA), an FDA-directed initiative, is specifically focused on improved preclinical assessment of torsade de pointes (TdP) risk, striving to optimize the drug discovery process.In recent years, human stem cell-derived cardiomyocytes have proven to recapitulate key features of human cardiac electrophysiology in vitro. Furthermore, it has become apparent that the intact ensemble of cardiac ion channels is necessary to determine proarrhythmic effects reliably. Hence, due to their relatively easy availability, stem cell-derived cardiomyocytes have become the preferred choice of cardiac cells.We present chip-based approaches allowing parallel patch clamp recordings without compromising data quality or technical sophistication. Culture and harvesting protocols have been optimized on cardiomyocytes for success rate but also the number of cells used.We show patch clamp data from two automated patch clamp platforms (medium throughput - Patchliner and high throughput - SyncroPatch 384/768PE). The Patchliner and the SyncroPatch 384/768PE both boast temperature control to enable recordings at physiological temperature - an important feature since drug efficacies may vary with temperature. Here, we present pharmacological data on voltage-dependent channels of the CiPA panel at different temperatures.The effect of drugs on action potentials is important for assessing the interaction of the cardiac ion channel ensemble. Both patch clamp platforms have amplifiers capable of current clamp. Compound effects on action potentials will also be presented.Patchliner and SyncroPatch 384/768PE are both planar patch-clamp platforms combining all the necessary features for successful drug discovery (well-suited for stem cell-derived cardiomyocytes, temperature control, and current clamp mode).