To provide a more thorough and predictive cardiac safety profile of new chemical entities, the FDA is introducing the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. To allow the successful integration of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) as a translational model of human cardiac tissue their physiology needs to be fully characterised.

There is a growing trend for utilisation of native human cells in drug discovery to overcome common translational disconnects between in vitro screening data, preclinical animal models, and clinical trials in man. Translational assays using cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) are increasingly appreciated as an accessible cell source for cardiac disease modelling, drug screening, and safety pharmacology.

The FDA’s Comprehensive in vitro Proarrythmia Assay (CiPA) initiative aims to provide a thorough preclinical cardiac safety profile of new chemical entities that enables prediction of human clinical proarrhythmia risk. To allow the successful utilisation of commercial human iPSC-derived cardiomyocytes (iPSC-CM) as models of human CM in the CiPA safety paradigm, their biophysical and pharmacological profile needs to be fully characterised. Here we will highlight our work to assess the utility of Axiogenesis vCor.4U iPSC-CM for CiPA-relevant cardiotoxicity screening.

Neurotoxicological effects now rank second behind cardiovascular events as adverse events impeding the development and safety of new drug candidates. Accordingly, Metrion has developed assays that can be used to predict seizurogenic and neurotoxic compound activity in the peripheral and central nervous system using native neurons, and are now building similar assays with human stem-cell derived neurons. Both approaches provide a translational step for development of anticonvulsant compounds and safe and effective treatments for other central nervous system diseases.

A number of different cell-based assays for cytotoxic effects of drugs exist including the lactate dehydrogenase (LDH) leakage assay, the neutral red assay, protein measurement and methyl tetrazolium (MTT) assay. We describe the development and optimization of a cell-based assay for cytotoxicity using impedance measurements. This assay is sensitive and provides reproducible results for safety pharmacology, toxicity screens of adherent, proliferating or non-proliferating cells. Changes in the impedance signal indicate effects on cell contractility, cell morphology and proliferation.

In depth profiling of human iPSC cardiomyocytes: From electrophysiology to phenotypic assays. Metrion’s Saïd El Haou presentation covers the topics of Manual Patch Clamp – Current Clamp, Axion Maestro – MEA and the Nanion CardioExcyte96 – Impedance.

Presentation from the Metrion Biosciences’ external speaker series, Professor Gary Stephens, University of Reading, 28th November 2016.

Metrion is working towards the requirements of the FDA’s Comprehensive in vitro Proarrhythmia (CiPA) initiative (cipaproject.org) which comprises 3 parts: 1) High quality in vitro cardiac ion channel assays, 2) Comprehensive in silico action potential (AP) models, and 3) Predictive assays using induced pluripotent stem cell derived cardiomyocytes (iPSC-CM).

To fulfil the last requirement of the CiPA initiative, the suitability and maturity of ventricular iPSC-CM need to be determined. In the current study, two ventricular iPSC- CM cell lines (LDN-1 and LDN-2) were generated and their molecular and biophysical properties compared with a commercial iPSC-CM cell line (COM-1) using three different methodologies.

Here, we have assessed the suitability of Axiogenesis CorV.4U 2nd generation iPSC-CM for cardiotoxicity screening by evaluating their biophysical and pharmacological characteristics using three different methodologies: