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Predictive Assays for High Throughput Assessment of Cardiac Toxicity and Drug Safety
Oksana Sirenko, Carole Crittenden, Jayne Hesley, Anson1, Yen-Wen Chen, Carlos Funes, and Evan F. Cromwell
Molecular Devices, LLC, 1311 Orleans Drive, Sunnyvale, CA 94089 1Cellular Dynamics International, 525 Science Drive, Madison, WI 53711
A large percentage of new drugs fail in clinical studies due to cardiac toxicity. Therefore development of highly predicative in vitro assays suitable for high throughput screening (HTS) is extremely important for drug development. Human cardiomyocytes derived from stem cell sources can greatly accelerate the development of new chemical entities and improve drug safety by offering more clinically relevant cell-based models than those presently available. Stem cell derived cardiomyocytes are especially attractive because they express ion channels and demonstrate spontaneous mechanical and electrical activity similar to native cardiac cells. Here we demonstrate cell based assays for measuring the impact of pharmacological compounds on the rate of beating cardiomyocytes with different assay platforms. Cardioactive compounds are used in clinical treatment of heart failure, arrhythmia or other cardiac diseases. Cardiac toxicity can cause arrhythmias or heart failure. We have shown dose-dependent atypical patterns caused by several cardiotoxic compounds and ion channel blockers. Also we have demonstrated effects of several positive (epinephrine, etc.) and negative (α and β blockers) chronotropic agents on cardiac rates and determined EC50s.

We developed methods for the ImageXpress® Micro and the FLIPR® Tetra systems that enable determination of beating rate from changes in intracellular CA2+ that are synchronous with beating. The protocols use induced pluripotent stem cells (iPCS) derived cardiomyocytes loaded with a calcium sensitive dye and allow monitoring of drug impact on the beat rate and amplitude in 96 or 384 well formats. Peak parameters are automatically measured using the Screenworks® Peak Pro™ software and proprietary analysis algorithms. We have demonstrated use of both systems for two important applications: screening compounds for cardiac toxicity, and preclinical testing of potential cardiac drug candidates. These methods are well suited for safety testing and can be used to estimate efficacy and dosing of drug candidates prior to clinical studies.
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