Metrion Biosciences independent analysis of the spontaneous and pacing stability of vCor.4UTM and their predictive response to selective pharmacological agents.
Extensive cardiac ion channel profiling at Metrion using selective pharmacological tools and manual patch clamp has enabled us to define the electrophysiological characteristics of vCor.4UTM human iPSC-derived cardiomyocytes (iPSC-CM). vCor.4UTM elicit spontaneous action potentials (AP) and can be paced at a range of frequencies (0.2 – 1 Hz).
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Overview
Extensive cardiac ion channel profiling at Metrion using selective pharmacological tools and manual patch clamp has enabled us to define the electrophysiological characteristics of vCor.4UTM human iPSC-derived cardiomyocytes (iPSC-CM).
vCor.4UTM elicit spontaneous action potentials (AP) and can be paced at a range of frequencies (0.2 – 1 Hz; Figure 1). The electrophysiological characteristics of evoked AP resemble primary human cardiomyocytes, with the cells having an average resting membrane potential of -73 mV and action potential duration at 90 % of repolarization (APD90) of 426 ms when paced at 1 Hz (Figure 1C).
vCor.4UTM AP are stable over time in both spontaneous and evoked recording conditions confirming the suitability of vCor. 4UTM for compound screening experiments (Figure 2). Additionally, we confirm that vCor.4UTM express a predominantly ventricular phenotype and exhibit the appropriate pharmacology in response to core cardiac channel modulators, including early after depolarizations (EADs) following IKr inhibition (Figure 3).
In the light of the incoming CiPA guidelines, Axiogenesis vCor. 4UTM iPSC-CM represent a suitable model for in vitro preclinical cardiac safety evaluation of compounds to identify potential human proarrhythmic liabilities.
We report the development and optimisation of a TREK-1 functional assay using the Qube 384, an automated patch clamp platform capable of supporting high-throughput screening. The assay was optimized to identify both activators and inhibitors on the same plate, providing key mechanistic data for high value, limited supply screening libraries such as venom fractions used in this study (Targeted Venom Discovery Array, TVDA, Venomtech, UK).
Current clamp recordings provide more physiologically relevant measurements of ion channel activity (in comparison to voltage clamp), allowing the contribution of different ion channel sub-types to resting membrane potential to be evaluated.