A mechanism-driven risk assessment approach combining ScreenSeq, HCI, and CaT predicted cardiotoxicity in hiPSC-CMs with 89% specificity, 91% sensitivity, and 90% accuracy.
A mechanism-driven approach combining structural, functional, and molecular high-throughput methods in hiPSC-CMs provides highly accurate pre-clinical cardiotoxicity risk assessment.
BACKGROUND: Cardiotoxicity remains one of the most reported adverse drug reactions that lead to drug attrition during pre-clinical and clinical drug development. Drug-induced cardiotoxicity may develop as a functional change in cardiac electrophysiology (acute alteration of the mechanical function of the myocardium) and/or as a structural change, resulting in loss of viability and morphological damage to cardiac tissue. RESEARCH DESIGN AND METHODS: transience (CaT) to analyze compound-treated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). RESULTS: Analysis of hiPSC-CMs treated with 33 cardiotoxicants and 9 non-cardiotoxicants of mixed therapeutic indications facilitated compound clustering by mechanism of action, scoring of pathway activities related to cardiomyocyte contractility, mitochondrial integrity, metabolic state, diverse stress responses and the prediction of cardiotoxicity risk. The combination of ScreenSeq, HCI and CaT provided a high cardiotoxicity prediction performance with 89% specificity, 91% sensitivity and 90% accuracy. CONCLUSIONS: Overall, this study introduces mechanism-driven risk assessment approach combining structural, functional and molecular high-throughput methods for pre-clinical risk assessment of novel compounds.
Rosell-Hidalgo et al. (Thu,) conducted a other in Drug-induced cardiotoxicity. Combination of ScreenSeq, HCI and CaT was evaluated on Cardiotoxicity prediction performance. A mechanism-driven risk assessment approach combining ScreenSeq, HCI, and CaT predicted cardiotoxicity in hiPSC-CMs with 89% specificity, 91% sensitivity, and 90% accuracy.