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Potentiator ivacaftor abrogates pharmacological correction of ?F508 CFTR in cystic fibrosis.


ABSTRACT: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR). Newly developed "correctors" such as lumacaftor (VX-809) that improve CFTR maturation and trafficking and "potentiators" such as ivacaftor (VX-770) that enhance channel activity may provide important advances in CF therapy. Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation (G551D) that affects only channel activity, a single compound is not sufficient to treat patients with the more common CFTR mutation, ?F508. Thus, patients with ?F508 will likely require treatment with both correctors and potentiators to achieve clinical benefit. However, whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro, the impact of chronic therapy has not been established. In studies of human primary airway epithelial cells, we found that both acute and chronic treatment with VX-770 improved CFTR function in cells with the G551D mutation, consistent with clinical studies. In contrast, chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated CFTR correction in ?F508 homozygous cultures. This result reflected the destabilization of corrected ?F508 CFTR by VX-770, markedly increasing its turnover rate. Chronic VX-770 treatment also reduced mature wild-type CFTR levels and function. These findings demonstrate that chronic treatment with CFTR potentiators and correctors may have unexpected effects that cannot be predicted from short-term studies. Combining these drugs to maximize rescue of ?F508 CFTR may require changes in dosing and/or development of new potentiator compounds that do not interfere with CFTR stability.

SUBMITTER: Cholon DM 

PROVIDER: S-EPMC4272825 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis.

Cholon Deborah M DM   Quinney Nancy L NL   Fulcher M Leslie ML   Esther Charles R CR   Das Jhuma J   Dokholyan Nikolay V NV   Randell Scott H SH   Boucher Richard C RC   Gentzsch Martina M  

Science translational medicine 20140701 246


Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR). Newly developed "correctors" such as lumacaftor (VX-809) that improve CFTR maturation and trafficking and "potentiators" such as ivacaftor (VX-770) that enhance channel activity may provide important advances in CF therapy. Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation (G551D) that affects only channel activity, a single compound is no  ...[more]

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