Abstract
Aims Loss-of-function mutations in the hERG gene causes long-QT syndrome type 2 (LQT2), a condition associated with reduced I Kr current. Four different mutation classes define the molecular mechanisms impairing hERG. Among them, Class 2 mutations determine hERG trafficking defects. Lumacaftor (LUM) is a drug acting on channel trafficking already successfully tested for cystic fibrosis and its safety profile is well known. We hypothesize that LUM might rescue also hERG trafficking defects in LQT2 and exert anti-arrhythmic effects. Methods and results From five LQT2 patients, we generated lines of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harbouring Class 1 and 2 mutations. The effects of LUM on corrected field potential durations (cFPD) and calcium-handling irregularities were verified by multi electrode array and by calcium transients imaging, respectively. Molecular analysis was performed to clarify the mechanism of action of LUM on hERG trafficking and calcium handling. Long-QT syndrome type 2 induced pluripotent stem cell-derived cardiomyocytes mimicked the clinical phenotypes and showed both prolonged cFPD (grossly equivalent to the QT interval) and increased arrhythmias. Lumacaftor significantly shortened cFPD in Class 2 iPSC-CMs by correcting the hERG trafficking defect. Furthermore, LUM seemed to act also on calcium handling by reducing RyR2 S2808 phosphorylation in both Class 1 and 2 iPSC-CMs. Conclusion Lumacaftor, a drug already in clinical use, can rescue the pathological phenotype of LQT2 iPSC-CMs, particularly those derived from Class 2 mutated patients. Our results suggest that the use of LUM in LQT2 patients not protected by β-blockers is feasible and may represent a novel therapeutic option.
| Original language | English |
|---|---|
| Pages (from-to) | 1446-1455 |
| Number of pages | 10 |
| Journal | European Heart Journal |
| Volume | 39 |
| Issue number | 16 |
| DOIs | |
| Publication status | Published - Apr 21 2018 |
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Keywords
- Antiarrhythmic therapy
- Arrhythmia
- Calcium regulation
- Long QT Syndrome 2
- Lumacaftor
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
Cite this
Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model. / Mehta, Ashish; Ramachandra, Chrishan J.A.; Singh, Pritpal; Chitre, Anuja; Lua, Chong Hui; Mura, Manuela; Crotti, Lia; Wong, Philip; Schwartz, Peter J.; Gnecchi, Massimiliano; Shim, Winston.
In: European Heart Journal, Vol. 39, No. 16, 21.04.2018, p. 1446-1455.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model
AU - Mehta, Ashish
AU - Ramachandra, Chrishan J.A.
AU - Singh, Pritpal
AU - Chitre, Anuja
AU - Lua, Chong Hui
AU - Mura, Manuela
AU - Crotti, Lia
AU - Wong, Philip
AU - Schwartz, Peter J.
AU - Gnecchi, Massimiliano
AU - Shim, Winston
PY - 2018/4/21
Y1 - 2018/4/21
N2 - Aims Loss-of-function mutations in the hERG gene causes long-QT syndrome type 2 (LQT2), a condition associated with reduced I Kr current. Four different mutation classes define the molecular mechanisms impairing hERG. Among them, Class 2 mutations determine hERG trafficking defects. Lumacaftor (LUM) is a drug acting on channel trafficking already successfully tested for cystic fibrosis and its safety profile is well known. We hypothesize that LUM might rescue also hERG trafficking defects in LQT2 and exert anti-arrhythmic effects. Methods and results From five LQT2 patients, we generated lines of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harbouring Class 1 and 2 mutations. The effects of LUM on corrected field potential durations (cFPD) and calcium-handling irregularities were verified by multi electrode array and by calcium transients imaging, respectively. Molecular analysis was performed to clarify the mechanism of action of LUM on hERG trafficking and calcium handling. Long-QT syndrome type 2 induced pluripotent stem cell-derived cardiomyocytes mimicked the clinical phenotypes and showed both prolonged cFPD (grossly equivalent to the QT interval) and increased arrhythmias. Lumacaftor significantly shortened cFPD in Class 2 iPSC-CMs by correcting the hERG trafficking defect. Furthermore, LUM seemed to act also on calcium handling by reducing RyR2 S2808 phosphorylation in both Class 1 and 2 iPSC-CMs. Conclusion Lumacaftor, a drug already in clinical use, can rescue the pathological phenotype of LQT2 iPSC-CMs, particularly those derived from Class 2 mutated patients. Our results suggest that the use of LUM in LQT2 patients not protected by β-blockers is feasible and may represent a novel therapeutic option.
AB - Aims Loss-of-function mutations in the hERG gene causes long-QT syndrome type 2 (LQT2), a condition associated with reduced I Kr current. Four different mutation classes define the molecular mechanisms impairing hERG. Among them, Class 2 mutations determine hERG trafficking defects. Lumacaftor (LUM) is a drug acting on channel trafficking already successfully tested for cystic fibrosis and its safety profile is well known. We hypothesize that LUM might rescue also hERG trafficking defects in LQT2 and exert anti-arrhythmic effects. Methods and results From five LQT2 patients, we generated lines of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harbouring Class 1 and 2 mutations. The effects of LUM on corrected field potential durations (cFPD) and calcium-handling irregularities were verified by multi electrode array and by calcium transients imaging, respectively. Molecular analysis was performed to clarify the mechanism of action of LUM on hERG trafficking and calcium handling. Long-QT syndrome type 2 induced pluripotent stem cell-derived cardiomyocytes mimicked the clinical phenotypes and showed both prolonged cFPD (grossly equivalent to the QT interval) and increased arrhythmias. Lumacaftor significantly shortened cFPD in Class 2 iPSC-CMs by correcting the hERG trafficking defect. Furthermore, LUM seemed to act also on calcium handling by reducing RyR2 S2808 phosphorylation in both Class 1 and 2 iPSC-CMs. Conclusion Lumacaftor, a drug already in clinical use, can rescue the pathological phenotype of LQT2 iPSC-CMs, particularly those derived from Class 2 mutated patients. Our results suggest that the use of LUM in LQT2 patients not protected by β-blockers is feasible and may represent a novel therapeutic option.
KW - Antiarrhythmic therapy
KW - Arrhythmia
KW - Calcium regulation
KW - Long QT Syndrome 2
KW - Lumacaftor
UR - http://www.scopus.com/inward/record.url?scp=85045680980&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045680980&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehx394
DO - 10.1093/eurheartj/ehx394
M3 - Article
AN - SCOPUS:85045680980
VL - 39
SP - 1446
EP - 1455
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
IS - 16
ER -