Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Na v 1.5 Function of Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A

• Published in: Circulation. Arrhythmia and electrophysiology Vol. 9; no. 11
• Main Authors: Kosmidis, Georgios, Veerman, Christiaan C., Casini, Simona, Verkerk, Arie O., van de Pas, Simone, Bellin, Milena, Wilde, Arthur A.M., Mummery, Christine L., Bezzina, Connie R.
• Format: Journal Article
• Language: English
• Published: 01.11.2016
• ISSN: 1941-3149; 1941-3084
• DOI: 10.1161/CIRCEP.116.004227

Background— Several compounds have been reported to induce translational readthrough of premature stop codons resulting in the production of full-length protein by interfering with ribosomal proofreading. Here we examined the effect of 2 of these compounds, gentamicin and PTC124, in human-induced pluripotent stem cell (hiPSC)–derived cardiomyocytes bearing nonsense mutations in the sodium channel gene SCN5A , which are associated with conduction disease and potential lethal arrhythmias. Methods and Results— We generated hiPSC from 2 patients carrying the mutations R1638X and W156X. hiPSC-derived cardiomyocytes from both patients recapitulated the expected electrophysiological phenotype, as evidenced by reduced Na + currents and action potential upstroke velocities compared with hiPSC-derived cardiomyocytes from 2 unrelated control individuals. While we were able to confirm the readthrough efficacy of the 2 drugs in Human Embryonic Kidney 293 cells, we did not observe rescue of the electrophysiological phenotype in hiPSC-derived cardiomyocytes from the patients. Conclusions— We conclude that these drugs are unlikely to present an effective treatment for patients carrying the loss-of-function SCN5A gene mutations examined in this study.