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Therapeutic potential of activators of two-pore domain ion channels

Presentation from Metrion Biosciences’ external speaker series, Professor Alistair Mathie, Medway School of Pharmacy, 13th October 2017.

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Electrophysiological characterisation of Cellular Dynamics International ventricular iCell2 iPSC-derived cardiomyocytes

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.

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Differentiation and validation of human iPSC-derived atrial cardiomyocytes

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.

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Comprehensive profiling of Axiogenesis ventricular vCor.4U iPSC-derived cardiomyocytes – from electrophysiology to phenotypic assays

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.

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Development of native and stem cell-derived electrophysiological assays for neurotoxicology screening and translational drug discovery

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.

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Monitoring drug-induced cytotoxicity and hepatotoxicity using impedance

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.

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In depth profiling of human iPSC cardiomyocytes: From electrophysiology to phenotypic assays

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.

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Modulation of voltage-gated calcium channels in disease

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

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CiPA update: Refining in vitro cardiac ion channel assays, in silico models and iPSC cardiomyocyte reagents for improved proarrhythmia risk prediction

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).

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Human ventricular stem cell cardiomyocytes: validating in vitro assays and screening platforms for proarrhythmia risk prediction

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.

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