Non-genetic all-optical assays
All-optical screening assays are designed to dynamically stimulate cells using light signals while monitoring the effects of new chemical entities (NCEs) using fluorescent reporters of the functional activity of cells. Not only “built-in” cell stimulation can significantly increase the predictive values of drug screening assays by reducing false positive/false negative hits, but it also can enable the discovery of NCEs with the use-dependent mechanism of action.
Use-dependent drugs are the most desirable drugs, because they only start working in pathological conditions when cells are activated. Since use-dependent drugs exhibit greater inhibition at faster stimulation rates7, without the ability to dynamically control the cellular activity during pharmacological profiling they are impossible to discover.
Drug-induced cardiotoxicity represents a major concern for our society. In the recent decades, several blockbuster drugs were removed from the market due to cardiac toxicity (i.e., their pro-arrhythmic effects), accounting for 30% of all post-approval withdrawals.
To address this possibly unwarranted drug attrition, the Comprehensive in vitro Pro-Arrhythmia (CiPA) initiative was launched. The goal of this initiative is to evaluate pro-arrhythmic risk based on mechanistic understanding of integrated drug effects on multiple human voltage-gated ion channels contributing to action potential in cardiomyocytes. The Component 3 of the CiPA initiative is aimed at in vitro verification of drug-induced pro-arrhythmic effects on human stem cell-derived cardiomyocytes using Microelectrode Arrays (MEAs) or imaging assays with voltage-sensitive probes.
Normal heart beating rates can vary almost two-fold in adults, and drugs can have different pro-arrhythmic effects across this range. Thus, in order for newly proposed in vitro assays to realistically recapitulate the in vivo cardiac activity, the ability to stimulate cardiomyocytes at desired frequencies during the in vitro assays is critical.
Positive outcomes: to increase the assay fidelity/predictiveness and to decrease the drug development costs.