FDA publication confirms Cor.4U as most predictive cardiac cell model

Two recent peer-reviewed publications underline the predictive value of Axiogenesis Cor.4U iPSC-derived cardiomyocytes (iPSC-CMs). Key observations and conclusions of these papers are discussed below.

FDA Publication: Comprehensive Translational Assessment of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias.

Ksenia Blinova and coworkers from FDA, as well as contributors from Zenas, University of Glasgow and Axion Biosciences, provide the to-date perhaps most comprehensive and clinically translational pharmacological assessment of iPSC-CMs.

In this report 26 drugs and 3 drug combinations, most with known QT prolongation and torsade de pointes (TdP) risk, were tested on iPSC-CM from two different commercial providers (Axiogenesis, CDI) using both high-throughput voltage-sensitive dye (VSD) and microelectrode-array (MEA) technologies. These assays are currently being validated for use in the Comprehensive in vitro Proarrhythmia Assay (CiPA). Importantly, the concentrations used in these experiments began at clinical (Cmax) values and were increased to supraphysiological doses as an example of a “safety margin” assessment. Ultimately, this study focused on the correlation of in vitro action potential (APD) and field potential (FPD) duration to clinical QT prolongation. These results were correlated with experimentally determined ion channel block to provide insight into iPSC-CMs as an integrative model demonstrating multiple ion channel effects (MICE).

 Table FDA paper iCell Cor.4U comparison

In the head-to-head comparison (see table above, reproduced from supplemental data, table IV), both cell types correctly did not identify any false positives (specificity = 1). Axiogenesis Cor.4U cardiomyocytes demonstrated better sensitivity than the iCells for predicting clinical APD90/FPDc prolongation as more true positives and fewer false negatives were identified.

Similarly, baseline inter- and intra-assay variation (COV) were also lower for Cor.4U as well and demonstrated good cross-platform consistency

Importantly, the dual blocker ranolazine did not elicit arrhythmias in Cor.4U cells, whereas it did at higher doses in the iCells. This is consistent with a previously characterized, detectable late sodium current in Cor.4U and underscores the need for a physiological cell system to assess Multiple Ion Channel Effects (MICE). 

For more details read the full article "Comprehensive Translational Assessment of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias" here

The Use of Ratiometric Fluorescence Measurements of the Voltage Sensitive Dye Di-4-ANEPPS to Examine Action Potential Characteristics and Drug Effects on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

This report evaluated the use of high bandwidth photometry applied to voltage-sensitive fluorescent dyes (VSDs) to assess drug-induced changes in action potential characteristics of spontaneously active hiPSC-CM.

The objective of the study was to demonstrate that optical VSD dye recording from hiPSC-derived cardiomyocytes is a suitably assay system for CiPA and for drug discovery. Using this assay, the authors compared electrophysiological characteristics of two commercially available hiPSC-derived cardiomyocytes cell types (Cor.4U and iCells), “both of which are thought to represent a stable paradigm of human-derived cardiomyocytes“.
The effect of 3 blinded reference compounds nifedipine (L-type calcium channel blocker), E-4031 (pure hERG blocker), and ranolazine (hERG and late sodium current blocker) were assessed.
Cor.4U and iCells responded similarly to nifedipine. However, only Cor.4U cells revealed a statistically relevant shortening of the APD90 at lower concentrations.
E-4031 induced similar APD90 prolongation in both cell types although iCells induced EADs already at 10 nM.
Ranolazine, a clinically safe drug, did not induce arrhythmias in Cor.4U even at the highest test dose of 100 µM - i.e. Cor.4U predicted the clinic accurately. In contrast, iCell cardiomyocytes reveal induction of EAD and tachy-arrhythmic beating patterns (see figure 9 of the paper, also summarized below).
An increased sensitivity to hERG blockers has been reported to be a hallmark of immature iPSC-derived cardiomyocytes.

Figure Cor.4U predictivity Clyde paper
According to the authors, “The mechanisms responsible for the complex cellular proarrhythmia observed with some (iCell) myocytes at supratherapeutic exposures of ranolazine are unclear.“

Taken together, the study by Hortigon-Vinagre clearly indicates that Cor.4U cardiomyocytes are the preferred cell model to assess cardiac pro-arrhythmic potential in vitro.

For more details read the full article here.

 

 

 

 

 

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