Graeme W Carlile1, Renaud Robert2, Julie Goepp2, Elizabeth Matthes2, Jie Liao2, Bart Kus3, Sean D Macknight4, Daniela Rotin3, John W Hanrahan2, David Y Thomas4. 1. Cystic Fibrosis Translational Research Center, Dept. of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada. Electronic address: graeme.carlile@mcgill.ca. 2. Cystic Fibrosis Translational Research Center, Dept. of Physiology, McGill University, Montreal, Quebec H3G1Y6, Canada. 3. Hospital for Sick Children, Dept. of Biochemistry, University of Toronto, Ontario M5G 1X8, Canada. 4. Cystic Fibrosis Translational Research Center, Dept. of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada.
Abstract
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.
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.
Authors: Ramanath Narayana Hegde; Seetharaman Parashuraman; Francesco Iorio; Fabiana Ciciriello; Fabrizio Capuani; Annamaria Carissimo; Diego Carrella; Vincenzo Belcastro; Advait Subramanian; Laura Bounti; Maria Persico; Graeme Carlile; Luis Galietta; David Y Thomas; Diego Di Bernardo; Alberto Luini Journal: Elife Date: 2015-12-23 Impact factor: 8.140