Mutation-specific Therapy for the Long QT Syndrome
Status:
Recruiting
Trial end date:
2023-12-31
Target enrollment:
Participant gender:
Summary
Novel therapy for the Long QT Syndrome based on the mechanism of action of the
disease-causing mutations
Long QT syndrome type 2 (LQT2) accounts for ~ 35% of all LQTS cases and is difficult to
manage, as beta-blockers frequently fail to provide full protection. Most LQT2 patients (pts)
have a Class 2 mutation, which implies defective "trafficking".
Lumacaftor (LUM) is a drug developed and currently indicated for the treatment of cystic
fibrosis (CF) in patients homozygous for the F508del mutation in the CFTR gene. LUM corrects
protein folding and trafficking defects of mutant and misfolded CFTR channels, restoring
their cell surface expression. The investigators recently demonstrated that LUM can rescue in
vitro the LQTS phenotype observed in human induced pluripotent stem cell- derived
cardiomyocytes (hiPSC-CMs) from pts with LQT2 Class 2 mutations (PMID: 29020304) and in these
same two patients Orkambi administrated for 7 days at the same dosage approved for cystic
fibrosis showed to reduce their QTc (PMID: 30753398).
With the present phase II clinical trial (MAST2) the investigators will enroll 20 LQT2
patients (see inclusion and exclusion criteria) and they will test in vivo the efficacy of
Orkambi in shortening their QTc. Patients will be admitted to hospital for a maximum of 7
days (minimum in-hospital stay based on evidence of QTc shortening). Orkambi will be
administered at the dose approved for cystic fibrosis and during the entire period continuous
ECG monitoring through both telemetry and 12-lead 24-hr Holter monitoring will be performed
and QTc length and morphology will be analyzed.