CARDIAC RISK ASSESSMENT IN HUMAN INDUCED PLURIPOTENT STEM CELL DERIVED CARDIOMYOCYTES

The investigation of the effects of new chemical entities (NCEs) on the extra-cellular field potential of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) is part of the new Comprehensive in vitro Proarrhythmia Assay (CiPA).

Porsolt is excited to announce the recent validation and addition of multi-electrode array (MEA) recording in hiPSC-CMs to its catalog. This further enhances our comprehensive cardiac electrophysiology offer, which already includes hERG (IKr), hNav1.5 (INa), hKir1.2 (IK1) and hCav1.2 (ICa) channel assays using patch-clamp technique or rabbit and dog Purkinje fiber studies.

Although patch-clamp studies remain an important part of cardiac safety testing, hiPSC-CMs allow an electrophysiological analysis not restricted to a single ion channel (e.g. hERG) and provide data on several parameters at the same time (depolarization, repolarization, arrhythmias...). hiPSC-CMs also provide a good alternative to ex vivo models and offer an additional 3R benefit for pharmaceutical preclinical safety screening. Both acute and long-term exposure experiments are also possible.

MEA technology allows for the recording of extra-cellular field potential waveforms from hiPSC-CMs monolayers which are analogous to clinical electrocardiogramm recording.

Analysis of the signal provides data on field potential duration (FPD, an analogue of the QT interval), spike amplitude, beat rate, and potential arrhythmias.

Field potentials are recorded from a spontaneously beating hiPSC-CMs monolayer (Cor 4U®, Axiogenesis, Germany) on the MEA-2100 system (Multi Channel Systems, Germany) using Cardio 2D software.

Cardiomyocytes plated on 6-well MEAs, 9 recording electrodes/well

Cardiomyocytes together with the capabilities of MEA platform provide important predictive cardiac electrophysiology data, matching the needs of the pharmaceutical industry to assess drug liability early in the drug discovery process.

EFFECTS OF CISAPRIDE (FROM 3 TO 300 nM) ON THE FIELD POTENTIAL DURATION LENGTHENING

Baselines values

Occurrence of arrhythmias after incubation with 300 nM cisapride (3 wells/4)

CONCENTRATION-DEPENDENT EFFECTS OF VERAPAMIL (3, 10, 30, 100 AND 300 nM) ON CORRECTED FIELD POTENTIAL DURATION (n=6 wells)

EFFECTS OF LIDOCAINE AT 100 µM ON THE SPIKE AMPLITUDE

> Proposed experimental protocols for your future studies

Number of wells Concentrations Vehicle control Reference substance Parameters Report
SCREENING n=3 5 cumulative concentrations No No FPD and FPDc
Beat rate
Spike amplitude (% change from baseline)

Arrhythmia
Rapidscreen
FULL STUDY n=6 5 cumulative concentrations Yes (5 time-matched periods) Yes (1 concentration) FPD and FPDc
Beat rate
Spike amplitude
Standard

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