[HTML][HTML] Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking
GW Carlile, R Robert, J Goepp, E Matthes, J Liao… - Journal of Cystic …, 2015 - Elsevier
GW Carlile, R Robert, J Goepp, E Matthes, J Liao, B Kus, SD Macknight, D Rotin…
Journal of Cystic Fibrosis, 2015•ElsevierBackground 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 …
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 …
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.
Elsevier
