Human iPSC-derived cardiomyocytes for cardiac proarrhythmic risk assessment

This webinar covered two assays developed by Eurofins – the Multi-Electrode Array (MEA) assay and the Calcium Transient FLIPR assay, which were made using induced pluripotent stem cell (iPSC) cardiomyocytes. The speaker discussed why these assays represent a more physiologic and dynamic system to provide a more comprehensive pre-clinical model for cardiac liability assessment.

Can the results from these assays replace clinical data?

Dr Verena Albert, Scientific Lead of the Cardiac Safety Services at Eurofins Discovery in San Diego: No, they cannot. Despite the fact that the phenotypic FLIPR Calcium flux assay is much closer to in vivo models, it is not designed to replace clinical data. However, it can be a very useful tool to aid during the drug discovery process and structure-activity relationship (SAR) information by providing more physiologically relevant data.

What are the currently recommended testing strategies under the CiPA initiative?

Verena: The CiPA initiative recommends a testing strategy focusing on four main points:

• First, all new drugs should be tested on seven relevant cardiac ion channel currents using in vitro cell-based models that overexpress the corresponding ion channels
• Second, the data obtained from the in vitro assays should be used to run in silico computer models to predict the clinical risk of arrhythmias
• As a third step, the effects of the new drugs on human stem cell derived cardiomyocytes should be tested by performing in vitro phenotypic assays on them in order to check for unanticipated effects
• Finally, the last step is to perform Phase I clinical trials where the focus should be on in vivo ECG biomarkers.

What is the turnaround time for the cardiomyocyte assays?

Verena: The turnaround time is 20 business days from when we have received all materials and documentation.

Do you also offer an assay in cardiomyocytes that uses voltage sensitive dyes?

Verena: At this point, we only offer the calcium flux assay that uses a calcium sensitive dye. If the main interest is to measure the current in the cardiomyocytes, the microelectrode array (MEA) is the most suitable assay as it records the field potential generated by the contracting cardiomyocytes.

Are the assays performed at physiological temperatures?

Verena: Yes they are. We perform the assays using the cardiomyocytes at 37°C. 

What do you think of testing the drugs on iPSC-derived cardiomyocytes from different donors (different ethnical backgrounds)?

Verena: It would be definitely very valuable to test drugs on iPSC-derived cardiomyocytes from different donors. It has been shown in the past that different ethnical backgrounds and gender can greatly influence the response to drugs.

Do you pace the cells in your assays?

Verena: No, the cells are not paced in the assay. Human iPSC-derived cardiomyocytes contract spontaneously and when cultured correctly, all cells in one well contract in a synchronous fashion.

Since calcium transients assessment is just a surrogate for contractility, is there a risk that we could miss any effects by not using a direct contractility test?

Verena: While it is true that measuring calcium transients is just a surrogate for contractility, we have obtained very reliable data with compounds that are known to affect cardiac function. The risk can certainly never be zero percent for potentially missing any effects, but according to the data that we have obtained so far, we believe that this risk is very small.