Referenced in: none

Automatically associated channels: Kv11.1 , Kv7.1

Title: Genome editing of isogenic human induced pluripotent stem cells recapitulates long QT phenotype for drug testing.

Authors: Yongming Wang, Ping Liang, Feng Lan, Haodi Wu, Leszek Lisowski, Mingxia Gu, Shijun Hu, Mark A Kay, Fyodor D Urnov, Rami Shinnawi, Joseph D Gold, Lior Gepstein, Joseph C Wu

Journal, date & volume: J. Am. Coll. Cardiol., 2014 Aug 5 , 64, 451-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25082577

Abstract
Human induced pluripotent stem cells (iPSCs) play an important role in disease modeling and drug testing. However, the current methods are time-consuming and lack an isogenic control.This study sought to establish an efficient technology to generate human PSC-based disease models with isogenic control.The ion channel genes KCNQ1 and KCNH2 with dominant negative mutations causing long QT syndrome types 1 and 2, respectively, were stably integrated into a safe harbor AAVS1 locus using zinc finger nuclease technology.Patch-clamp recording revealed that the edited iPSC-derived cardiomyocytes (iPSC-CMs) displayed characteristic long QT syndrome phenotype and significant prolongation of the action potential duration compared with the unedited control cells. Finally, addition of nifedipine (L-type calcium channel blocker) or pinacidil (KATP-channel opener) shortened the action potential duration of iPSC-CMs, confirming the validity of isogenic iPSC lines for drug testing in the future.Our study demonstrates that iPSC-CM-based disease models can be rapidly generated by overexpression of dominant negative gene mutants.