Evaluation of a novel CFTR potentiator in copd ferrets with acquired cftr dysfunction.

Academic Article


  • 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.
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    Digital Object Identifier (doi)

    Pubmed Id

  • 28154177
  • Author List

  • Kaza N; Lin VY; Stanford D; Hussain SS; Libby EF; Kim H; Borgonovi M; Conrath K; Mutyam V; Byzek SA