Chronic Cardiotoxicity Assay: hiPSC Derived Cardiomyocytes
Measure the potential for test compounds to become trapped inside the hERG channel pore
Base impedance, an indicator of cell viability, can be used to non-invasively identify structural and functional cardiotoxicity over a chronic time course.
We have developed a chronic cardiotoxicity assay using human iPSC-derived cardiomyocytes, which has been validated with a number of cardiotoxicants. For example, doxorubicin, a member of the anthracycline family that is used to treat breast cancer, is associated with a number of cardiac side effects, which includes acute atrial and ventricular arrhythmias, chronic cardiomyopathy and congestive heart failure.
This chronic cardiotoxicity assay recapitulates doxorubicin’s cardiotoxic effect by producing a concentration-dependent decrease of base impedance that develops following a 24 hour exposure period.
This protocol is designed to measure the potential for test compounds to become trapped inside the hERG channel pore, and it is the first to be validated on an automated patch clamp platform.
Ion channel screening resource library
Publications
- Ion Channel Drug Discovery and Modern Medicine.
- Ion Channel Discovery – Partnering to Access Specialized Expertise.
- Recent advances in electrophysiology-based screening technology and the impact upon ion channel discovery research.
- Clathrodin, hymenidin and oroidin, and their synthetic analogues as inhibitors of the voltage-gated potassium channels.
- Novel K+ Channel Targets in Atrial Fibrillation Drug Development – Where Are We?
- Human Electrophysiological and Pharmacological Properties of XEN-D0101: A Novel Atrial-Selective Kv1.5/IKur Inhibitor.
Videos and Presentations
- Designing multiple assay protocols for ligand gated ion channels using the stacked-tip feature on the Patchliner and SP384i platforms
- The benefits of targeting ion channels for pain and some of the hurdles in developing successful ion channel modulators.
Posters
- 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.
- The development of a set of novel small molecule inhibitors of the Kv1.3 ion channel.
- 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.
Application notes and resources
- ASIC1a Ligand Gated Ion Channel Assay (App Note)
- Investigating the correlation between thallium flux and automated patch-clamp for ion channel activators.
- Identification of novel ion-channel binders: TRPA1 antagonist case study.
- The development of a set of novel small molecule inhibitors of the Kv1.3 ion channel.
- Cross-site and cross-platform variability of automated patch clamp assessments of drug effects on human cardiac currents in recombinant cells.
- A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm
- The Nav 1.5 Late Current in WT and Nav 1.5 ΔKPQ Mutant Channels: An Automated Patch Clamp LQT3 Electrophysiological Assay Comparison. Safety Pharmacology Society Virtual Meeting 2020.
- NaV1.5-ΔKPQ late INa current properties and pharmacology on the SyncroPatch 384i
- Recent advances in targeting ion channels to treat chronic pain.
- Marc Rogers (Metrion Director and Former CSO) takes part in a collaborative webinar with Nanion Technologies entitled “Validation and optimization of automated patch clamp voltage-gated Ca2+ channel assays”.
- Open access to the KCNQ channel: Retigabine and second generation M-current openers.
- Development of native and stem cell-derived electrophysiological assays for neurotoxicology screening and translational drug discovery
- Characterization of Endogenous Sodium Channels in the ND7-23 Neuroblastoma Cell Line: Implications for Use as a Heterologous Ion Channel Expression System Suitable for Automated Patch Clamp Screening.
- Optimising a difficult Nav1.8 cell line assay for automated patch clamp screening. Ion Channel Retreat, Vancouver, 2015
- Synthesis and biological evaluation of piperazine derivatives as novel isoform selective voltage-gated sodium (Nav) 1.3 channel modulators
- Action of Clathrodin and Analogues on Voltage-Gated Sodium Channels
- Novel state-dependent voltage-gated sodium channel modulators, based on marine alkaloids from Agelas sponges
- Ligand- and structure-based virtual screening for clathrodin-derived human voltage-gated sodium channel modulators
- The role of Nav1.7 in human nociceptors: insights from human induced pluripotent stem cell-derived sensory neurons of erythromelalgia patients
- Assessment of human induced pluripotent stem cell-derived cardiomyocytes for evaluating drug-induced arrhythmias with multi-electrode array
- Development of an impedance based screening assay for cardiac safety and cardiotoxicity detection in stem cell derived cardiomyocytes
- Validation of an impedance-based phenotypic screening assay able to detect multiple mechanisms of chronic cardiotoxicity in human stem cell-derived cardiomyocytes
- Electrophysiological characterisation of Cellular Dynamics International ventricular iCell2 iPSC-derived cardiomyocytes
- Functional characterisation of human iPSC-derived atrial cardiomyocytes
Let’s work together
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