High throughput all optical assay in human cardiomyoctes for clinically relevant prediction of drug induced cardiotoxity

DESCRIPTION provided by applicant Toxicity accounts for approximately of drug attrition of which nearly one third is attributed to cardiovascular issues in particular arrhythmias The cost of bringing a new drug to market can exceed $ billion and require more than years of research Thus it is critical to identify cardiotoxicity early in developmen Current in vitro screening assays for pro arrhythmic drug effects focus on measuring inhibition of the hERG potassium channel which has been linked to potentially lethal Torsades de Pointes arrhythmias TdP The hERG assay however lacks high sensitivity and specificity not all QT prolongation is due to block of hERG alone and not all hERG blockers result in QT prolongation or induce TdP To address these limitations regulatory bodies have created the Comprehensive in vitro Proarrhythmia Assay CiPA initiative which proposes use of cardiomyocytes derived from human stem cells as an in vitro model for arrhythmogenic drug potential Establishment of this model for toxicity screening requires detailed characterization of the cardiomyocyte action potential AP and calcium transient CT the response of APs CTs to drugs and the correlation to clinical outcomes in humans High throughput tools needed for performing these measurements however have been lacking Here we propose to develop a high throughput all optical electrophysiology platform for cardiotoxicity screening in sem cell derived cardiomyocytes With our Phase I award we demonstrated that the Optopatch platform could be used to detect changes in the electrophysiological characteristics of human derived CMs following both acute and chronic drug treatment albeit with the throughput of a single well per recording To highly parallelize these measurements we propose building a well plate Optopatch instrument for simultaneous recording of voltage and calcium waveforms under paced conditions from wells This geometry will provide nearly two orders of magnitude improvement in throughput of our assay Optopatch constructs will be optimized to allow for incorporation of the actuator and reporter proteins in each cell We will utilize this platform to screen compounds with known risk scores for Torsades de Pointes in different sources of human cardiomyocytes and use this data to develop a predictive algorithm of arrhythmogenicity PUBLIC HEALTH RELEVANCE Q Stateandapos s technology will allow better prediction of a drug candidateandapos s potential adverse effects to the human heart than the assays mandated by the current cardiac safety guidance ICH S B It will contribute to bringing effective healthcare solutions to market at lower cost and higher productivity by preventing drugs with cardiotoxicity from reaching the market and preventing the development of valuable therapeutics from being wrongly terminated which is one of the concerns about the current S B assays Making Q State instrumentation and reagents available to the academic research community will facilitate better mechanistic studies and therapeutics development to benefit patients with cardiac conditions