Platform for High-Throughput Cardiotoxicity Drug Screening

Principal Investigator:

David J. Christini, Adjunct Professor of Physiology and Biophysics

Technology Summary

This technology is an optical dynamic clamp (ODC) platform that enables light-activated current generation in iPSC-derived cardiomyocytes, making them a suitable platform for cardiotoxicity screening.

Technology Overview

Cardiovascular toxicity is a leading cause of drug development failure and market withdrawal across multiple drug classes including anti-cancer, antibiotics, antidepressants, and antipsychotics. Drug safety regulations mandate cardiac testing of all drug candidates. Current platforms for preclinical cardiotoxicity screening largely rely on nonhuman models that do not faithfully recapitulate human physiology. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are a renewable source of human cardiomyocytes for preclinical studies and can be derived from target patient populations. However, iPSC-CMs exhibit low levels of the inward rectifier potassium current, leading to an immature electrophysiological phenotype and limiting their relevance to adult arrhythmogenesis. Electrode-based dynamic clamp (EDC) is used to inject current and produce more adult-like electrophysiology in iPSC-CMs, but this technology does not scale for high-throughput applications.

Cornell inventors developed an optical dynamic clamp (ODC) which uses light to deliver the current necessary to induce adult-like action potential morphology in iPSC-CMs in a precise and contactless manner. Similar to EDC, ODC is able to inhibit spontaneous activity, allowing for accurate measurement of AP characteristics. These results are consistent at different frequencies and in the presence of ion-channel modulators, validating the use of ODC as a platform for high-throughput cardiotoxicity drug screening.

Potential Applications