Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes

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Matsa, Elena, Dixon, James E., Medway, Christopher, Georgiou, Orestis, Patel, Minal J., Morgan, Kevin, Kemp, Paul J., Staniforth, Andrew, Mellor, Ian and Denning, Chris (2013) Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes. European Heart Journal . ISSN 0195-668X

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Official URL: http://eurheartj.oxfordjournals.org/content/early/2013/03/06/eurheartj.eht067.full

Abstract

Aims Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS.

Methods and results We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K+ currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations).

Conclusions These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart.

Item Type:	Article
RIS ID:	https://nottingham-repository.worktribe.com/output/713897
Keywords:	iPS cells, Long-QT syndrome, Arrhythmia, Electrophysiology, Gene therapy
Schools/Departments:	University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine
Identification Number:	10.1093/eurheartj/eht067
Depositing User:	Chamberlain, Mr Dick
Date Deposited:	15 Apr 2014 12:04
Last Modified:	04 May 2020 16:36
URI:	https://eprints.nottingham.ac.uk/id/eprint/2664

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