摘要

AIMS: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.
METHODS AND RESULTS:After hospital admission and 1 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. Lumacaftor + Ivacaftor shortened QTc significantly in both patients: in V6 from 551 ± 22 ms to 523 ± 35 ms in Patient 1 (Pt1) and from 472 ± 21 ms to 449 ± 20 ms in Patient 2 (Pt2); in DII from 562 ± 25 ms to 549 ± 35 ms in Pt1 and from 485 ± 32 ms to 452 ± 18 ms in Pt2. 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. On treatment, both patients developed diarrhoea, Pt1 more than Pt2.
CONCLUSION:This represents the first attempt to validate in patients the in vitro results of a drug repurposing strategy for cardiovascular disorders. Lumacaftor + Ivacaftor 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.

译文

目的: 已经表明 Lumacaftor 挽救了两个 LQT2 患者的诱导多能干细胞来源的心肌细胞 (iPSC-CMs) 中的 hERG 运输缺陷, 我们测试了商业协会 Lumacaftor Ivacaftor (LUM IVA) 是否能缩短同一两名患者的 QTc。
方法和结果: 在入院和基线记录 1 天后，在第 1 天给半剂量 LUM IVA，然后给全剂量 (LUM 800 mg IVA 500 mg)，持续 7 天。连续 12 导联动态心电图允许大量盲 QTc 测量。两名患者的 Lumacaftor Ivacaftor QTc 均显著缩短: 在患者 1 (Pt1) 中，V6 的 QTc 从毫秒缩短到毫秒; 在患者 2 (Pt2) 中，从毫秒缩短到毫秒; 在从 562 ± 25 ms DII，549 ± 35 ms Pt1 中并从 485 ± 32 ms 到 452 ± 18 ms Pt2. 中在这两种患者中，较低水平的 QTc 值百分比显著增加: 在 V6 中从 33% 增加到 68%，从 33% 增加到 76%; 在 DII 中从 33% 增加到 50%，从 33% 增加到 87%。在冲洗期间，观察到 QTc 的反弹。在治疗中，两个病人都出现腹泻，Pt1 比 pt2 多。
结论: 这是首次尝试在患者身上验证心血管疾病药物再利用策略的体外结果。Lumacaftor Ivacaftor 显著缩短了两例有贩运缺陷的 LQT2 患者的 QTc，在很大程度上证实了他们的 iPSC-CMs 中的发现，但有较小的数量变化。这些发现令人鼓舞，但如果没有更多患者的验证，立即转化为临床实践还为时过早。