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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 Ca 2+  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.

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