CardioXpress: new high throughput early cardiac drug testing assay
12 Sep 2012

Detecting the early onset of promising compounds' adverse effects on the cardiac function remains a challenge in the drug discovery & development process. Current model systems, essentially animal-based, have their limitations. There is an urgent and unmet need for reliable cardiac assays mimicking the complex ion-channel interactions of cardiomyocytes in the human heart. Such a solution, capable of identifying risks and revealing underlying mechanistic interactions in early drug development phases, will considerably reduce animal use, R&D time and cost to market.

The project

NOTOCORD® is convinced that experimental results from cellular approaches will weight more and more in the decision making process.
Our goal being to provide the most reliable tools on latest technology, NOTOCORD® partnered with Multi Channel Systems and Pluriomics to create the CardioXpress project: a new platform dedicated to the analysis of field potential on human pluripotent stem cells cardiomyocytes (hPSC-CM). This Eurostars-labeled project receives funding from the Eureka network, a guarantee of high-quality and innovation.

Human pluripotent stem cells are a renewable and reproducible source of hPSC-CM sharing many features with human adult ventricular cardiomyocytes1. The potential of disease models based on hPSC-CM has been convincingly proven in a number of scientific publications1, 2, 3.
Records and analysis of hPSC-CM responses at different doses of potential drugs, associated to multi-well micro-electrode arrays and advanced software will be used to predict the effect of compounds on cardiac electrical activity and consequently so cardiac risks (see figure below).

Example disruptions of cardiac electrical activity

The images above shows different cardiac electrical disruptions, from prolongation to fibrillation (in vitro). Prolonged fieldpotential due to block of hERG currents by increasing concentrations of E-4031 (A) evokes a transition to proarrhythmic events (B). In another in vitro experiment a Torsade like form arrhythmia could be evoked with a high concentration of a hERG channel blocking drug (C).

The Consortium

Pluriomics will develop its StemCARDcells technology to meet the required biological criteria. Their objective is to overcome the variability problem and to deliver high quality hPSC-CM, differentiated and maintained in completely defined, serum free culture media.
Multi Channel Systems will develop a novel automated platform technology for electrophysiological screening of hPSC-CM in 24 or 96 multi-wells plates. The system will offer pure digital gain, filter and bandwidth control. It will be able to accept liquid handling robot to enable automated unsupervised experimental routines.
NOTOCORD® will develop advanced acquisition of signals up to complete analysis. Our objective is to provide you the easiest way to control such sophisticated technology, with a full integrated solution from experiment management to data collection and meta-analysis.

 

References

1- Braam SR, Tertoolen LL, van de Stolpe A., Meyer T, Passier R and Mummery CL (2010). Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Stem Cell Research 4, 107–116.
2- Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, Feldman O, Gepstein A, Arbel G, Hammerman H et al. (2011). Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225–229.
3- Liang H, Matzkies M, Schunkert H, Tang M, Bonnemeier H, Hescheler J and Reppel M (2010). Human and murine embryonic stem cell-derived cardiomyocytes serve together as a valuable model for drug safety screening. Cell Physiol Biochem 25, 459–466.