Automated Electrophysiology Assessment of Drug induced Cardiotoxicity Based on Parallel Noninvasive Nanoelectrode Array

Summary
Drug safety issues pose a serious challenge to the health and well being of patients The
development of our innovative technology aims to address a significant gap in the in vitro
assessment of drug induced cardiotoxicity which is the number one reason for withdrawals of
all marketed drugs as well as the premature termination of promising drug development
candidates Pressured by the enormous social and economic consequence today s drug safety
professionals are facing daunting challenges to improve accuracy in predicting the cardiac
liability of candidate drugs increase assay throughput to afford earlier evaluation of larger
number of compounds and reduce assay cost to mitigate the fast rising spending on drug
development
Recent advances in human stem cell derived cardiomyocyte hSC CM research demonstrate
significant advantages over traditional in vitro model such as immortalized hERG cell lines
Compared to single parameter hERG assay hSC CM provides an integrated action potential a
powerful biomarker for arrhythmia from an intact human based physiologic system In addition
the potential ability to generate unlimited patient specific induced pluripotent stem cell iPSC
CM opens a tantalizing opportunity to model disease for individual patients and for preclinical
human trials that would closely reflect the diversity of drug responses in the entire population
This has prompted an FDA initiative Comprehensive In vitro Proarrhythmia Assessment or
CiPA that proposes the use of hSC CMs for the electrophysiological assessment of
proarrhythmia risk a primary form of cardiotoxicity for all drugs
Yet despite the pressing need to meet FDA s impending regulatory requirements drug safety
professionals do not have an effective technology that affords high data quality single cell
resolution physiological relevance long term measurement high throughput and low cost
analysis of transmembrane action potential from hSC CM Existing technologies namely the
patch clamp for intracellular electrophysiology and the planar multiple electrode array MEA
for extracellular electrophysiology addresses either data quality or throughput to an extent but
never both The lack of adequate environmental control for both technologies further reduces
the physiological relevance of the results
The novel electrophysiology platform proposed in this STTR application provides a powerful
solution that bridges the longstanding gap between high quality low throughput intracellular
electrophysiology and low quality high throughput extracellular electrophysiology and for the
first time enables the measurement of hSC CMs under optimal physiological conditions Central
to this system is the seamless integration of two innovative approaches parallel nano
fabricated biocompatible electrodes and sensitive environmentally robust electronics In
combination our breakthrough technology provides a significantly improved cellular
electrophysiology platform with an immediate and positive impact on the cardiotoxicity
assessment using human stem cell derived cardiomyocytes This tool with further development
can afford requirements for even higher throughput and other electrophysiology applications
such as network analysis using stem cell derived neurons Public Health Relevance
Accurate prediction of drug safety remains one of the greatest challenges for efficient and cost effective
development of safe pharmaceuticals This study aims to develop a fully automated electrophysiology system
based on a novel nano fabricated electrode array for conducting drug safety assays using human pluripotent
stem cell derived cardiomyocytes hPSC CM