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Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model.

Abstract

Aims

Loss-of-function mutations in the hERG gene causes long-QT syndrome type 2 (LQT2), a condition associated with reduced IKr current. Four different mutation classes define the molecular mechanisms impairing hERG. Among them, Class 2 mutations determine hERG trafficking defects. Lumacaftor (LUM) is a drug acting on channel trafficking already successfully tested for cystic fibrosis and its safety profile is well known. We hypothesize that LUM might rescue also hERG trafficking defects in LQT2 and exert anti-arrhythmic effects.

Methods and results

From five LQT2 patients, we generated lines of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harbouring Class 1 and 2 mutations. The effects of LUM on corrected field potential durations (cFPD) and calcium-handling irregularities were verified by multi electrode array and by calcium transients imaging, respectively. Molecular analysis was performed to clarify the mechanism of action of LUM on hERG trafficking and calcium handling. Long-QT syndrome type 2 induced pluripotent stem cell-derived cardiomyocytes mimicked the clinical phenotypes and showed both prolonged cFPD (grossly equivalent to the QT interval) and increased arrhythmias. Lumacaftor significantly shortened cFPD in Class 2 iPSC-CMs by correcting the hERG trafficking defect. Furthermore, LUM seemed to act also on calcium handling by reducing RyR2S2808 phosphorylation in both Class 1 and 2 iPSC-CMs.

Conclusion

Lumacaftor, a drug already in clinical use, can rescue the pathological phenotype of LQT2 iPSC-CMs, particularly those derived from Class 2 mutated patients. Our results suggest that the use of LUM in LQT2 patients not protected by β-blockers is feasible and may represent a novel therapeutic option.

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  • Authors+Show Affiliations

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    National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore. Cardiovascular Academic Clinical Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.

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    National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.

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    National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.

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    National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.

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    National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.

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    Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS, Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy. Department of Cardiothoracic and Vascular Sciences-Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy. Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Viale Golgi, 19, 27100, Pavia, Italy.

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    Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Viale Golgi, 19, 27100, Pavia, Italy. IRCCS Istituto Auxologico Italiano, San Luca Hospital, Piazzale Brescia 20, 20149 Milan, Italy. IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, via Pier Lombardo 22, 20135 Milan, Italy.

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    Department of Cardiology, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.

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    IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, via Pier Lombardo 22, 20135 Milan, Italy.

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    Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS, Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy. Department of Cardiothoracic and Vascular Sciences-Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy. Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Viale Golgi, 19, 27100, Pavia, Italy. Department of Medicine, University of Cape Town, Old main Building, J-Floor Groote Schuur Hospital Observatory Cape Town 7925, South Africa.

    National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore. Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.

    Source

    European heart journal : 2017 Jul 21 pg

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    29020304