title: Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy.
abstract: Recently approved therapies that modulate CFTR function have shown significant clinical benefit, but recent investigations regarding their molecular mechanism when used in combination have not been consistent with clinical results. We employed micro-optical coherence tomography as a novel means to assess the mechanism of action of CFTR modulators, focusing on the effects on mucociliary clearance. Primary human airway monolayers from patients with a G551D mutation responded to ivacaftor treatment with increased ion transport, airway surface liquid depth, ciliary beat frequency, and mucociliary transport rate, in addition to decreased effective viscosity of the mucus layer, a unique mechanism established by our findings. These endpoints are consistent with the benefit observed in G551D patients treated with ivacaftor, and identify a novel mechanism involving mucus viscosity. In monolayers derived from F508del patients, the situation is more complicated, compounded by disparate effects on CFTR expression and function. However, by combining ion transport measurements with functional imaging, we establish a crucial link between in vitro data and clinical benefit, a finding not explained by ion transport studies alone. We establish that F508del cells exhibit increased mucociliary transport and decreased mucus effective viscosity, but only when ivacaftor is added to the regimen. We further show that improvement in the functional microanatomy in vitro corresponds with lung function benefit observed in the clinical trials, whereas ion transport in vitro corresponds to changes in sweat chloride. Functional imaging reveals insights into clinical efficacy and CFTR biology that significantly impact our understanding of novel therapies.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Susan E
authors.initials: SE
authors.lastname: Birket
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; and.
authors.forename: Kengyeh K
authors.initials: KK
authors.lastname: Chu
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Grace H
authors.initials: GH
authors.lastname: Houser
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts;
authors.forename: Linbo
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Fernandez
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: George M
authors.initials: GM
authors.lastname: Solomon
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Vivian
authors.initials: V
authors.lastname: Lin
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Suresh
authors.initials: S
authors.lastname: Shastry
authors.affiliation: Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Marina
authors.initials: M
authors.lastname: Mazur
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sloane
authors.affiliation: Center for Nanomedicine, Department of Ophthalmology, and Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; and.
authors.forename: Guillermo J
authors.initials: GJ
authors.lastname: Tearney
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Cellular, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama; smrowe@uab.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000627:Aminophenols / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D065101:Chloride Channel Agonists / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D015363:Quinolones / Q000494:pharmacology*
chemical_list: D000627:Aminophenols; C505032:CFTR protein, human; D065101:Chloride Channel Agonists; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; C545203:ivacaftor; D000584:Amiloride
keywords: mucociliary transport