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

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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 + 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.

Original languageEnglish
Pages (from-to)1832-1836
Number of pages5
JournalEuropean Heart Journal
Volume40
Issue number23
DOIs
Publication statusPublished - Jun 14 2019

Fingerprint

Long QT Syndrome
Induced Pluripotent Stem Cells
Cardiac Myocytes
Drug Repositioning

Keywords

  • Drug repurposing
  • Human-induced pluripotent stem cells
  • Life-threatening arrhythmias
  • Long QT syndrome
  • Lumacaftor
  • Mutation-specific therapy
  • Precision medicine
  • Sudden death
  • Trafficking defect

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{a2599fb7d242485faac06ddde98b2988,
title = "From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2",
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 + 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.",
keywords = "Drug repurposing, Human-induced pluripotent stem cells, Life-threatening arrhythmias, Long QT syndrome, Lumacaftor, Mutation-specific therapy, Precision medicine, Sudden death, Trafficking defect",
author = "Schwartz, {Peter J.} and Massimiliano Gnecchi and Federica Dagradi and Silvia Castelletti and Gianfranco Parati and Carla Spazzolini and Luca Sala and Lia Crotti",
year = "2019",
month = "6",
day = "14",
doi = "10.1093/eurheartj/ehz023",
language = "English",
volume = "40",
pages = "1832--1836",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "23",

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TY - JOUR

T1 - From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2

AU - Schwartz, Peter J.

AU - Gnecchi, Massimiliano

AU - Dagradi, Federica

AU - Castelletti, Silvia

AU - Parati, Gianfranco

AU - Spazzolini, Carla

AU - Sala, Luca

AU - Crotti, Lia

PY - 2019/6/14

Y1 - 2019/6/14

N2 - 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.

AB - 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.

KW - Drug repurposing

KW - Human-induced pluripotent stem cells

KW - Life-threatening arrhythmias

KW - Long QT syndrome

KW - Lumacaftor

KW - Mutation-specific therapy

KW - Precision medicine

KW - Sudden death

KW - Trafficking defect

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U2 - 10.1093/eurheartj/ehz023

DO - 10.1093/eurheartj/ehz023

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JO - European Heart Journal

JF - European Heart Journal

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