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Identification of novel ion-channel binders: TRPA1 antagonist case study (Collaboration with Domainex)

Domainex and Metrion Biosciences have formed an alliance to identify new chemical hits against ion-channel targets. Key to this collaboration are Domainex’s experience in hit identification and Metrion Bioscience’s expertise in ion channel screening and pharmacology.

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Identification of novel scorpion venom peptide inhibitors of the Kv1.3 ion channel and their potential as drug discovery leads for human T-cell mediated disease

Activated effector memory T-cells (TEM) have been implicated in the pathogenesis of autoimmune diseases.1 Activated TEM cells express high levels of the voltage-gated potassium channel Kv1.3, which functions to control cell excitability.

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Assessment of human induced pluripotent stem cell-derived cardiomyocytes for evaluating drug-induced arrhythmias with multi-electrode array

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) are a promising tool for assessment of drug-induced arrhythmias during non-clinical drug development. This technology is under evaluation by the FDA’s Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative and the Japanese iPS Cardiac Safety Assessment consortium (JiCSA) to develop new cardiac safety assessment measures to refine current S7B and E14 guidelines.

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New CiPA cardiac ion channel cell lines and assays for in vitro proarrhythmia risk assessment

New cardiac safety testing guidelines are being finalised, as part of the FDA’s Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, which aim to remove the over-reliance on screening against the hERG channel by expanding the panel to include hNav1.5, hCav1.2, hKv4.3/KChiP2.2, hKir2.1 and hKv7.1/KCNE1 human cardiac ion channels.

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A drug discovery collaboration between Japanese pharma and a UK SME CRO successfully developed novel small molecule inhibitors of the Kv1.3 channel to treat autoimmune disease

The Best of Both Worlds: Innovation, Collaboration and Synergy between CROs and their Customer Partners, Stevenage, 2018

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Functional characterisation of human iPSC-derived atrial cardiomyocytes

Atrial fibrillation (AF) is the most common arrhythmia observed in the clinic, considerable effort has been made to identify the cellular mechanisms of AF and develop new safe and effective antiarrhythmic drugs(1). However, preclinical studies using non-cardiac cells and non-human animal models may not replicate the physiology of human atrial cardiomyocytes or predict patient efficacy and safety.

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Refining in vitro QPatch cardiac ion channel QPatch and MEA iPSC cardiomyocyte assays for CiPA

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is a new cardiac safety testing proposal sponsored by the FDA to refine the current ICH S7B and E14 guidelines. Two components of CiPA utilise in vitro electrophysiological assays that require validation using a toolbox of compounds with defined clinical proarrhythmic risk. Here we outline our progress to optimise these electrophysiological assays to meet the CiPA goal of predicting human cardiac liability.

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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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