Modeling susceptibility to drug-induced long QT with a panel of subject-specific induced pluripotent stem cells

• DOI: 10.7554/elife.19406
• Publication Date: 2017-01-30T11:00:11Z
• Authors: Francesca Stillitano; Jens Hansen; Chi-Wing Kong; Ioannis Karakikes; Christian Funck-B...; Lin Geng; Stuart Scott; Stephan Reynier; Ma Wu; Yannick Valogne; Carole Desseaux; Joe-Elie Salem; Dorota Jeziorowska; Noël Zahr; Ronald Li; Ravi Iyengar; Roger J Hajjar; Jean-Sébastien Hulot
• Keywords: Sotalol; Safety pharmacology; Drug Development

A large number of drugs can induce prolongation cardiac repolarization and life-threatening arrhythmias. The prediction this side effect is however challenging as it usually develops in some genetically predisposed individuals with normal at baseline. Here, we describe a platform based on diverse panel induced pluripotent stem cells (iPSCs) that reproduces susceptibility to develop cardiotoxic drug response. We generated iPSC-derived cardiomyocytes from patients presenting vivo extremely low or high changes response pharmacological challenge sotalol. In vitro, the responses sotalol were highly variable but strongly correlated inter-individual differences observed vivo. Transcriptomic profiling identified dysregulation genes ( DLG2, KCNE4, PTRF, HTR2C , CAMKV ) involved downstream regulation machinery underlying sensitivity Our findings offer novel insights for development iPSC-based screening assays testing individual reactions.