Targeting ion channels in cystic fibrosis

J Cyst Fibros. 2015 Sep;14(5):561-70. doi: 10.1016/j.jcf.2015.06.002. Epub 2015 Jun 23.


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.

Keywords: Alternative chloride channels; CFTR modulators; ENaC; Pharmacotherapy; SLC26A9; TMEM16A.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aminophenols / therapeutic use*
  • Anoctamin-1
  • Antiporters / drug effects
  • Antiporters / metabolism
  • Chloride Channels / drug effects
  • Chloride Channels / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / drug effects*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / genetics
  • Cystic Fibrosis* / metabolism
  • Epithelial Sodium Channels / drug effects
  • Epithelial Sodium Channels / metabolism
  • Humans
  • Ion Transport / genetics
  • Mutation / drug effects
  • Neoplasm Proteins / drug effects
  • Neoplasm Proteins / metabolism
  • Quinolones / therapeutic use*
  • Sulfate Transporters


  • ANO1 protein, human
  • Aminophenols
  • Anoctamin-1
  • Antiporters
  • CFTR protein, human
  • Chloride Channels
  • Epithelial Sodium Channels
  • Neoplasm Proteins
  • Quinolones
  • SLC26A9 protein, human
  • Sulfate Transporters
  • Cystic Fibrosis Transmembrane Conductance Regulator