Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function

Abstract Background Ivacaftor (KALYDECO™, VX-770) is a CFTR potentiator that increased CFTR channel activity and improved lung function in patients age 6 years and older with CF who have the G551D-CFTR gating mutation. The aim of this in vitro study was to evaluate the effect of ivacaftor on mutant...

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Bibliographic Details
Published in:Journal of cystic fibrosis 2014-01, Vol.13 (1), p.29-36
Main Authors: Van Goor, Fredrick, Yu, Haihui, Burton, Bill, Hoffman, Beth J
Format: Article
Language:English
Subjects:
Aminophenols - pharmacology
Animals
Cell Line
CFTR
Chlorides - metabolism
Cystic Fibrosis - drug therapy
Cystic Fibrosis - genetics
Cystic Fibrosis - metabolism
Cystic Fibrosis Transmembrane Conductance Regulator - agonists
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Humans
In Vitro Techniques
Ion Channel Gating - drug effects
Ion Channel Gating - genetics
Ivacaftor
Mutation, Missense
Potentiator
Pulmonary/Respiratory
Quinolones - pharmacology
Rats
Rats, Inbred F344
Thyroid Gland - cytology
VX-770
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Summary:Abstract Background Ivacaftor (KALYDECO™, VX-770) is a CFTR potentiator that increased CFTR channel activity and improved lung function in patients age 6 years and older with CF who have the G551D-CFTR gating mutation. The aim of this in vitro study was to evaluate the effect of ivacaftor on mutant CFTR protein forms with defects in protein processing and/or channel function. Methods The effect of ivacaftor on CFTR function was tested in electrophysiological studies using a panel of Fischer rat thyroid (FRT) cells expressing 54 missense CFTR mutations that cause defects in the amount or function of CFTR at the cell surface. Results Ivacaftor potentiated multiple mutant CFTR protein forms that produce functional CFTR at the cell surface. These included mutant CFTR forms with mild defects in CFTR processing or mild defects in CFTR channel conductance. Conclusions These in vitro data indicated that ivacaftor is a broad acting CFTR potentiator and could be used to help stratify patients with CF who have different CFTR genotypes for studies investigating the potential clinical benefit of ivacaftor.
ISSN:1569-1993
1873-5010
DOI:10.1016/j.jcf.2013.06.008