Human iPSC-derived Cardiomyocytes: a Predictive, HTS-Scalable Tool for Comprehensive Cardiac Safety/Toxicity Assessment
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1
Axiogenesis AG, Germany
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2
Axiogenesis AG, Germany
A major hurdle to overcome in drug development is drug-induced hERG block leading to QT-prolongation and their association with potentially life threatening ventricular cardiac arrhythmias, a.k.a. Torsade-des-Pointes (TdP). The FDA/HESI/CSRC has sponsored the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative - a new model for a mechanistic approach to cardiac safety testing that improves upon existing methodologies (i.e. hERG testing) to better predict proarrhythmic activity through the use of ion channel screening, computer modeling, and stem cell derived cardiomyocytes. Outside of CiPA and arrhythmia concerns, structural cardiotoxicity or chronic dosing effects on intracellular signaling pathways are still of great concern as these effects can influence lead candidate selection dramatically. Thus, the development of novel cardiotox screening platforms to enhance drug discovery during early preclinical development is of great value to potentially reduce costly downstream attrition. Here we present work with Cor.4U, human induced pluripotent stem cell (iPSC) cardiomyocytes, used to compare the effects of dofetilide, E-4031, flecainide, moxifloxacin, ranolazine, quinidine, nifedipine, verapamil, TTX, and ATX II reference compounds on various device platforms, including microelectrode array (MEA) recordings. These data collectively show the flexibility and predictivity of human iPSC - derived cardiomyocytes as a HTS-scalable tool for comprehensive cardiac risk assessment.
Keywords:
cardiomyocytes,
cardiotoxicity,
IPSC,
CIPA,
cardiac safety testing
Conference:
MEA Meeting 2016 |
10th International Meeting on Substrate-Integrated Electrode Arrays, Reutlingen, Germany, 28 Jun - 1 Jul, 2016.
Presentation Type:
oral
Topic:
MEA Meeting 2016
Citation:
Kettenhofen
R,
Duenbostell
A,
Rascher-Eggstein
G and
Bohlen
H
(2016). Human iPSC-derived Cardiomyocytes: a Predictive, HTS-Scalable Tool for Comprehensive Cardiac Safety/Toxicity Assessment.
Front. Neurosci.
Conference Abstract:
MEA Meeting 2016 |
10th International Meeting on Substrate-Integrated Electrode Arrays.
doi: 10.3389/conf.fnins.2016.93.00006
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Received:
22 Jun 2016;
Published Online:
24 Jun 2016.
*
Correspondence:
Dr. Ralf Kettenhofen, Axiogenesis AG, Köln, Germany, ralf.kettenhofen@ncardia.com