Background: Small molecules as shown by VX809 can rescue the mislocalization of F508del-CFTR. The aim of this study was to identify correctors with a clinical history and their targets of action. Methods: CFTR correctors were screened using two F508del-CFTR expressing cell based HTS assays. Electrophysiological studies using CFBE41o- and HBE cells and in-vivo mouse assays confirmed CFTR rescue. The target of action was attained using pharmacological inhibitors and siRNA to specific genes. Results: Ibuprofen was identified as a CFTR corrector. Ibuprofen treatment of polarized CFBE41o- monolayers increased the short-circuit current (Isc) response to stimulation. In vivo CF mice treatment with ibuprofen restored the CFTR trafficking. SiRNA knock down of cyclooxygenase expression caused partial F508del-CFTR correction. Conclusion: These studies show that ibuprofen is a CFTR corrector and that it causes correction by COX-1 inhibition. Hence ibuprofen may be suitable to be part of a future CF combination therapy.
CITATION STYLE
Carlile, G. W., Robert, R., Goepp, J., Matthes, E., Liao, J., Kus, B., … Thomas, D. Y. (2015). Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking. Journal of Cystic Fibrosis, 14(1), 16–25. https://doi.org/10.1016/j.jcf.2014.06.001
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