JAN 14, 2020 8:00 AM PST

CiPA initiative and validation of high-throughput methods to characterize compound effects in human iPSC-derived cardiomyocytes

Speakers
  • Senior Scientist, Eurofins Discovery
    Biography
      "Rengi" Renganathan received his PhD at Madurai Kamaraj University, Madurai, India in 1990. With different post-doctoral experiences in Na+ current and Ca2+ current, he has acquired extensive experience in ion channel electrophysiology. He has 38 publications on ion channels. He has 18 years of experience in preclinical cardiac safety.
    • Senior Scientist-Group Leader, Cell-based Screening, Eurofins Discovery
      Biography
        Panida Lertkiatmongkol earned her PhD in Pharmacology and Toxicology from Medical College of Wisconsin in 2017. With a decade of experience in cell-based assays, she has been in charge of assay development for innovation projects and high-throughput screening campaigns. She also oversees routine safety pharmacology panel screening. Cardiotoxic pharmacology profiling is one of her innovation projects. For this study, she performs calcium flux assay using hiPSC-derived cardiomyocytes as a model to assess potential cardiotoxicity of compounds.
      • Senior Research Scientist, Molecular Devices
        Biography
          Oksana Sirenko earned her PhD in Biochemistry from the Biochemistry Research Institute, Academy of Sciences in Ukraine. For over 15 years, she has worked as a Research Scientist in cell-based assay development, drug discovery, and drug development in several pharma and biotech companies including Novartis, Bayer, and Fibrogen. At Molecular Devices she is focused on assay development using high-content imaging systems and other instruments to develop methods for cell-based disease modeling and toxicity research.
        • Applications Scientist, Molecular Devices
          Biography
            Carole Crittenden has a B.S. in Biology from Oral Roberts University. At the Fred Hutchinson Cancer Center in Seattle, WA, she was involved in assay development and bone marrow transplantation research. At the biotechnology companies Cell Therapeutics and Molecumetics, she focused on assay development and GPCR-based high-throughput screening. Since 2002, she has been involved in the development of three FLIPR high-throughput screening systems, and other instrument and reagent projects at Molecular Devices.

          Abstract

          DATE: January 14, 2020

          TIME:  8:00 am PST, 4:00 pm GMT, 5:00 pm CET

           

          Drug-induced QT interval prolongation and Torsades de Pointes (TdP) arrhythmias are the leading causes for drug withdrawals from market and compound attrition during drug development. To assess potential cardiotoxicity of compounds, Comprehensive in vitro Proarrhythmia Assay (CiPA) is the new cardiac safety testing paradigm that includes in vitro assays using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). To adopt this paradigm, we developed a high-throughput hiPSC-CM assay using calcium-sensitive dyes that exhibit fast kinetic fluorescence detected by the high-speed fluorescence imaging platform, the FLIPR® Penta High-Throughput Cellular Screening System.

          In this webinar, we will show data on evaluated concentration-dependent responses of 28 pharmacological agents linked to low, intermediate, and high TdP risk categories. Compound-induced proarrhythmic effects such as changes in beating rate and durations of these 28 agents were quantified and reported by monitoring changes in intracellular Ca2+ oscillations. Characterization of calcium oscillations allowed us to evaluate complex waveforms and events. In addition to changes in peak frequency and amplitude, we observed compound-induced proarrhythmic effects, peak prolongations, as well as increased complexity of patterns and appearance of secondary peaks at concentrations that correlated to clinically-relevant concentrations of QT prolongation and TdP arrhythmias. We characterized waveform irregularities using ScreenWorks® Peak Pro 2 software to obtain more than 20 dose-dependent readouts. Moreover, we assessed cellular and mitochondrial toxicity of these 28 compounds in the follow-up assay using the ImageXpress® Micro Confocal High-Content Imaging System to simultaneously monitor acute & chronic dosing effects of structural cardiotoxicity with multiple toxicity indicators. Taken together, we demonstrate that our high-throughput assay can provide an in vitro drug-induced proarrhythmia assessment as part of the cardiac safety paradigm encouraged by the CiPA initiative, and strengthens pharmacological safety profiles of drug candidates.

           

          Learning Objectives:

          • Discuss the latest news on the CiPA initiative
          • Discuss how to evaluate compound induced effects on hiPSC-derived cardiomyocytes
          • Summarize new features of the FLIPR Penta System and ScreenWorks Peak Pro 2 software

           

          Webinars will be available for unlimited on-demand viewing after live event.

           

          LabRoots is approved as a provider of continuing education programs in the clinical laboratory sciences by the ASCLS P.A.C.E. ® Program. By attending this webinar, you can earn 1 Continuing Education credit once you have viewed the webinar in its entirety.


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