@article {Kaza2101581, author = {Niroop Kaza and Vivian Y. Lin and Denise Stanford and Shah S. Hussain and Emily Falk Libby and Harrison Kim and Monica Borgonovi and Katja Conrath and Venkateshwar Mutyam and Stephen A. Byzek and Li Ping Tang and John E. Trombley and Lawrence Rasmussen and Trenton Schoeb and Hui Min Leung and Guillermo J. Tearney and S. Vamsee Raju and Steven M. Rowe}, title = {Evaluation of a novel CFTR potentiator in copd ferrets with acquired cftr dysfunction}, elocation-id = {2101581}, year = {2021}, doi = {10.1183/13993003.01581-2021}, publisher = {European Respiratory Society}, abstract = {Rationale. The majority of chronic obstructive pulmonary disease (COPD) patients have chronic bronchitis, for which specific therapies are unavailable. Acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is observed in chronic bronchitis, but has not been proven in a controlled animal model with airway disease. Furthermore, the potential of CFTR as a therapeutic target has not been tested in vivo, given limitations to rodent models of COPD. Ferrets exhibit cystic fibrosis-related lung pathology when CFTR is absent and COPD with bronchitis following cigarette smoke exposure.Objectives. To evaluate CFTR dysfunction induced by smoking and test its pharmacologic reversal by a novel CFTR potentiator, GLPG2196, in a ferret model of COPD with chronic bronchitis.Methods. Ferrets were exposed for six months to cigarette smoke to induce COPD and chronic bronchitis and then treated with eneral GLPG2196 once daily for one month. Electrophysiologic measurements of ion transport and CFTR function, assessment of mucociliary function by one-micron optical coherence tomography imaging and particle tracking microrhelogy, microcomputed tomography imaging, histopathological analysis, and quantification of CFTR protein and mRNA expression were used to evaluate mechanistic and pathophysiological changes.Measurements and Main Results. Following cigarette smoke exposure, ferrets exhibited CFTR dysfunction, increased mucus viscosity, delayed mucociliary clearance, airway wall thickening, and airway epithelial hypertrophy. In COPD ferrets, GLPG2196 treatment reversed CFTR dysfunction, increased mucus transport by decreasing mucus viscosity, and reduced brochial wall thickening and airway epithelial hypertrophy.Conclusions. The pharmacologic reversal of acquired CFTR dysfunction is beneficial against pathologic features of chronic bronchitis in a COPD ferret model.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Borgonovi has nothing to disclose.Conflict of interest: Dr. Conrath reports personal fees from Galapagos, during the conduct of the study; .Conflict of interest: Dr. Byzek has nothing to disclose.}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/early/2021/11/18/13993003.01581-2021}, eprint = {https://erj.ersjournals.com/content/early/2021/11/18/13993003.01581-2021.full.pdf}, journal = {European Respiratory Journal} }