From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2

<strong>Aims</strong>: Having shown that Lumacaftor rescued the hERG trafficking defect in the induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two LQT2 patients, we tested whether the commercial association Lumacaftor+Ivacaftor (LUM+IVA) could shorten the QTc in the same two patients. <strong>Methods and Results</strong>: After hospital admission and one day of baseline recordings, half dose LUM+IVA was administered on day 1, followed by full dose (LUM 800 mg + IVA 500 mg) for 7 days. A continuous 12-lead Holter ECG allowed a large number of blind QTc measurements. LUM+IVA shortened QTc significantly in both patients: in V6 from 551±22 to 523±35 ms in Patient1, and from 472±21 to 449±20 ms in Patient2; in DII from 562±25 to 549±35 ms in Patient1, and from 485±32 to 452±18 ms in Patient2. In both patients the percentage of QTc values in the lower tertile increased strikingly: in V6 from 33% to 68% and from 33% to 76%; in DII from 33% to 50% and from 33% to 87%. In the wash-out period a rebound in QTc was observed. Patient1 more than Patient2 developed diarrhoea during the study. <strong>Conclusion</strong>: This represents the first attempt to validate in patients the <em>in vitro</em> results of a drug repurposing strategy for cardiovascular disorders. LUM+IVA shortened significantly the QTc in the two LQT2 patients with a trafficking defect, largely confirming the findings in their iPSC-CMs but with smaller quantitative changes. The findings are encouraging but immediate translation into clinical practice, without validation in more patients, would be premature.