Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy

Ioannis Karakikes, Francesca Stillitano, Mathieu Nonnenmacher, Christos Tzimas, Despina Sanoudou, Vittavat Termglinchan, Chi-Wing Kong, Stephanie Rushing, Jens Hansen, Delaine Ceholski, Fotis Kolokathis, Dimitrios Kremastinos, Alexandros Katoulis, Lihuan Ren, Ninette Cohen, Johannes M.I.H. Gho, Dimitrios Tsiapras, Aryan Vink, Joseph C. Wu, Folkert W. Asselbergs, Ronald A. Li, Jean-Sebastien Hulot, Evangelia G. Kranias and Roger J. Hajjar ()
Additional contact information
Ioannis Karakikes: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Francesca Stillitano: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Mathieu Nonnenmacher: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Christos Tzimas: Molecular Biology, Biomedical Research Foundation of the Academy of Athens
Despina Sanoudou: University of Athens
Vittavat Termglinchan: Stanford University School of Medicine
Chi-Wing Kong: Stem Cell & Regenerative Medicine Consortium, LKS Faculty of Medicine, University of Hong Kong
Stephanie Rushing: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Jens Hansen: Systems Biology Center New York, Icahn School of Medicine at Mount Sinai
Delaine Ceholski: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Fotis Kolokathis: Attikon Hospital, University of Athens
Dimitrios Kremastinos: Attikon Hospital, University of Athens
Alexandros Katoulis: Attikon Hospital, University of Athens
Lihuan Ren: Stem Cell & Regenerative Medicine Consortium, LKS Faculty of Medicine, University of Hong Kong
Ninette Cohen: Icahn School of Medicine at Mount Sinai
Johannes M.I.H. Gho: University Medical Centre Utrecht
Dimitrios Tsiapras: Ona ssis Cardiac Surgery Center
Aryan Vink: University Medical Center Utrecht, PO Box 85500, 3508 GA
Joseph C. Wu: Stanford University School of Medicine
Folkert W. Asselbergs: University Medical Centre Utrecht
Ronald A. Li: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Jean-Sebastien Hulot: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Evangelia G. Kranias: Molecular Biology, Biomedical Research Foundation of the Academy of Athens
Roger J. Hajjar: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract A number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (PLN) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhythmias. Here we generate induced pluripotent stem cells (iPSCs) from a patient harbouring the PLN R14del mutation and differentiate them into cardiomyocytes (iPSC-CMs). We find that the PLN R14del mutation induces Ca2+ handling abnormalities, electrical instability, abnormal cytoplasmic distribution of PLN protein and increases expression of molecular markers of cardiac hypertrophy in iPSC-CMs. Gene correction using transcription activator-like effector nucleases (TALENs) ameliorates the R14del-associated disease phenotypes in iPSC-CMs. In addition, we show that knocking down the endogenous PLN and simultaneously expressing a codon-optimized PLN gene reverses the disease phenotype in vitro. Our findings offer novel strategies for targeting the pathogenic mutations associated with cardiomyopathies.

Date: 2015
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DOI: 10.1038/ncomms7955

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