Novel applications of automated electrophysiology in ion channel drug discovery

In this two-part webinar, we will be presenting the following topics in ion channel drug discovery.

Topic 1: Novel high-throughput approach to evaluate state dependence and selectivity of voltage-gated ion channels

Speaker: Rok Cerne, Ph.D, Principal Research Scientist, Eli Lilly and Company

Voltage-gated ion channels represent important drug targets. Current drug discovery efforts targeting ion channels often focus on identifying state -dependent inhibitors, and these characterizations are traditionally done using manual patch-clamp methods. Automated electrophysiology assays were introduced to increase the throughput of electrophysiological profiling, however these assays typically relay on pulse based protocols where compound potency is affected by the mechanism of channel gating and the kinetics of compound binding.
In this webinar, a novel high-throughput approach is presented using automated electrophysiology. This assay allowed for robust assessment of state-dependent effects of test agents and enabled direct comparison of compound potency across several ion channel subtypes at equivalent levels of inactivation. In addition to determination of state dependency and selectivity, the assay provided valuable information on the kinetics of compound association and dissociation. 

Learning Objectives:

• Learn about  continuous holding of membrane potential on a high throughput automated electrophysiology instrument
• Learn about measurement of compound effects across several ion channel subtypes at equivalent level of inactivation

Topic 2: Validating cardiac ion channels using automated electrophysiology for the CiPA paradigm

Speaker: Haiyang (David) Wei, Ph.D, Team Lead Scientist, Eurofins Pharma Discovery Services

Drug-induced QT interval prolongation and Torsades de Pointes (TdP) arrhythmia are the leading causes for drug withdrawal from the market. For the past decade, in vitro hERG channel assays and in vivo QT measurements have been conducted as surrogates for proarrhythmic risk propensity according to ICH S7B and ICH E14 guidelines. This paradigm, although effective, suffered from lack of specificity and led to unnecessary compound attrition during drug development. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) is a new cardiac safety testing paradigm intended to address this limitation with improved prediction of drug’s proarrhythmic liability. This new paradigm includes a panel of in vitro assays that integrates effects of the test compounds on several cardiac ion channels.
In this study, three cardiac ionic currents (IKr, ICa, INa, fast) were validated on a novel microfluidic-based automated patch clamp system to evaluate accuracy, precision and robustness of the assays. The results demonstrate suitability of the system for high throughput screening of drug effects on cardiac ionic currents, and provide data for in silico reconstructions in the CiPA paradigm for defining proarrhythmic risk.

Learning Objectives:

• Learn about the in vitro assay panel on cardiac ion channels relating to the CiPA paradigm
• Learn about the application of automated patch clamp in assessing cardiac ionic currents