Presentation from the Metrion Biosciences’ external speaker series, Professor Gary Stephens, University of Reading, 28th November 2016.

Metrion is working towards the requirements of the FDA’s Comprehensive in vitro Proarrhythmia (CiPA) initiative (cipaproject.org) which comprises 3 parts: 1) High quality in vitro cardiac ion channel assays, 2) Comprehensive in silico action potential (AP) models, and 3) Predictive assays using induced pluripotent stem cell derived cardiomyocytes (iPSC-CM).

To fulfil the last requirement of the CiPA initiative, the suitability and maturity of ventricular iPSC-CM need to be determined. In the current study, two ventricular iPSC- CM cell lines (LDN-1 and LDN-2) were generated and their molecular and biophysical properties compared with a commercial iPSC-CM cell line (COM-1) using three different methodologies.

Here, we have assessed the suitability of Axiogenesis CorV.4U 2nd generation iPSC-CM for cardiotoxicity screening by evaluating their biophysical and pharmacological characteristics using three different methodologies:

For CiPA, iPSC-CMs expressing a mature ventricular phenotype are required. At Metrion Biosciences we have focused on electrophysiological profiling of Axol Human iPSC-Derived Ventricular Cardiomyocytes (hiPSC-vCMs) by evaluating their biophysical and pharmacological characteristics.

Presentation by Marc Rogers (Metrion CSO) at the June 2016 Sophion Ion Channel Modulation Symposium, Clare College, Cambridge (UK). CiPA update: in vitro cardiac ion channel screens, in silico models and stem cell iPS cardiomyocyte assays for proarrhythmia risk prediction.

Voltage-dependent sodium channels (Nav) are implicated in a wide range of diseases, with their role in triggering and modulating membrane excitability making them key drug discovery targets for cardiac and neurological indications. Neuronal Nav’s are divided into TTX-sensitive (Nav1.1, Nav1.2, Nav1.3, Nav1.6 and Nav1.7) and TTX-resistant channels (Nav1.8 and Nav1.9), with those found in the CNS underlying various types of epilepsy and those expressed in the periphery implicated in many types of pain behaviour such as inflammatory, neuropathic, chemotherapy and cancer-induced pain, as well as visceral pain conditions such as irritable bowel syndrome (IBS). 

Rogers, M.; Zidar, N.; Kikelj, D.; Kirby, R.W. Assay and Drug Development Technologies. 2016, 14 (2),109-130

El-Haou, S.; Ford, J.; Milnes, J. Journal of Cardiovascular Pharmacology. 2015, 66 (5), 412-431

Presentation by Marc Rogers (Metrion CSO) at the September 2015 Safety Pharmacological Society, Prague. Using high quality HTS automated patch-clamp data from human cardiac ion channels and in silico action potential modelling to cost-effectively predict QP prolongation and arrhythmia risk for CiPA.