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

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.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC4149735 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Wang Yongming Y   Liang Ping P   Lan Feng F   Wu Haodi H   Lisowski Leszek L   Gu Mingxia M   Hu Shijun S   Kay Mark A MA   Urnov Fyodor D FD   Shinnawi Rami R   Gold Joseph D JD   Gepstein Lior L   Wu Joseph C JC  

Journal of the American College of Cardiology 20140801 5

<h4>Background</h4>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.<h4>Objectives</h4>This study sought to establish an efficient technology to generate human PSC-based disease models with isogenic control.<h4>Methods</h4>The ion channel genes KCNQ1 and KCNH2 with dominant negative mutations causing long QT syndrome types 1 and 2, respectively, were stably integr  ...[more]

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