title: Targeting ion channels in cystic fibrosis.
abstract: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause a characteristic defect in epithelial ion transport that plays a central role in the pathogenesis of cystic fibrosis (CF). Hence, pharmacological correction of this ion transport defect by targeting of mutant CFTR, or alternative ion channels that may compensate for CFTR dysfunction, has long been considered as an attractive approach to a causal therapy of this life-limiting disease. The recent introduction of the CFTR potentiator ivacaftor into the therapy of a subgroup of patients with specific CFTR mutations was a major milestone and enormous stimulus for seeking effective ion transport modulators for all patients with CF. In this review, we discuss recent breakthroughs and setbacks with CFTR modulators designed to rescue mutant CFTR including the common mutation F508del. Further, we examine the alternative chloride channels TMEM16A and SLC26A9, as well as the epithelial sodium channel ENaC as alternative targets in CF lung disease, which remains the major cause of morbidity and mortality in patients with CF. Finally, we will focus on the hurdles that still need to be overcome to make effective ion transport modulation therapies available for all patients with CF irrespective of their CFTR genotype.
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany; Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics, University of Heidelberg, Heidelberg, Germany. Electronic address: Marcus.Mall@med.uni-heidelberg.de.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy. Electronic address: galietta@unige.it.
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
mesh_terms: D000627:Aminophenols / Q000627:therapeutic use*; D000075369:Anoctamin-1; D017920:Antiporters / Q000187:drug effects / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D009154:Mutation / Q000187:drug effects; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000627:therapeutic use*; D000076988:Sulfate Transporters
chemical_list: C476213:ANO1 protein, human; D000627:Aminophenols; D000075369:Anoctamin-1; D017920:Antiporters; C505032:CFTR protein, human; D018118:Chloride Channels; D053503:Epithelial Sodium Channels; D009363:Neoplasm Proteins; D015363:Quinolones; C455628:SLC26A9 protein, human; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: Alternative chloride channels; CFTR modulators; ENaC; Pharmacotherapy; SLC26A9; TMEM16A