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 þ Ivacaftor (LUM þ IVA) could shorten the QTc in the same two patients. Methods After hospital admission and 1 day of baseline recordings, half dose LUM þ IVA was administered on Day 1, fol- and results lowed by full dose (LUM 800 mg þ IVA 500 mg) for 7 days. A continuous 12-lead Holter ECG allowed a large number of blind QTc measurements. Lumacaftor þ 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 þ 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.

Schwartz, P., Gnecchi, M., Dagradi, F., Castelletti, S., Parati, G., Spazzolini, C., et al. (2019). From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2. EUROPEAN HEART JOURNAL, 40(23), 1832-1836 [10.1093/eurheartj/ehz023].

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

Parati, G;Sala, L;Crotti, L
2019

Abstract

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 þ Ivacaftor (LUM þ IVA) could shorten the QTc in the same two patients. Methods After hospital admission and 1 day of baseline recordings, half dose LUM þ IVA was administered on Day 1, fol- and results lowed by full dose (LUM 800 mg þ IVA 500 mg) for 7 days. A continuous 12-lead Holter ECG allowed a large number of blind QTc measurements. Lumacaftor þ 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 þ 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.
Articolo in rivista - Articolo scientifico
Drug repurposing; Human-induced pluripotent stem cells; Life-threatening arrhythmias; Long QT syndrome; Lumacaftor; Mutation-specific therapy; Precision medicine; Sudden death; Trafficking defect;
Long QT syndrome, Human-induced pluripotent stem cells, Mutation-specific therapy, Trafficking defect, Drug repurposing, Precision medicine, Lumacaftor, Sudden death, Life-threatening arrhythmias
English
6-feb-2019
2019
40
23
1832
1836
reserved
Schwartz, P., Gnecchi, M., Dagradi, F., Castelletti, S., Parati, G., Spazzolini, C., et al. (2019). From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2. EUROPEAN HEART JOURNAL, 40(23), 1832-1836 [10.1093/eurheartj/ehz023].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/220000
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