The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

Curr Opin Pharmacol. 2018 Dec;43:152-165. doi: 10.1016/j.coph.2018.09.007. Epub 2018 Oct 16.


Cystic fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR dysfunction is characterized by abnormal mucociliary transport due to a dehydrated airway surface liquid (ASL) and hyperviscous mucus, among other pathologies of host defense. ASL depletion is caused by the absence of CFTR mediated chloride secretion along with continued activity of the epithelial sodium channel (ENaC) activity, which can also be affected by CFTR mediated anion conductance. Therefore, ENaC has been proposed as a therapeutic target to ameliorate ASL dehydration and improve mucus transport. Inhibition of ENaC has been shown to restore ASL hydration and enhance mucociliary transport in induced models of CF lung disease. To date, no therapy inhibiting ENaC has successfully translated to clinical efficacy, in part due to concerns regarding off-target effects, systemic exposure, durability of effect, and adverse effects. Recent efforts have been made to develop novel, rationally designed therapeutics to produce-specific, long-lasting inhibition of ENaC activity in the airways while simultaneously minimizing off target fluid transport effects, systemic exposure and side effects. Such approaches comprise next-generation small molecule direct inhibitors, indirect channel-activating protease inhibitors, synthetic peptide analogs, and oligonucleotide-based therapies. These novel therapeutics represent an exciting step forward in the development of ENaC-directed therapies for CF.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis / physiopathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Diffusion of Innovation
  • Drug Design
  • Epithelial Sodium Channel Blockers / adverse effects
  • Epithelial Sodium Channel Blockers / therapeutic use*
  • Epithelial Sodium Channels / drug effects*
  • Epithelial Sodium Channels / metabolism
  • Genetic Predisposition to Disease
  • Humans
  • Lung / drug effects*
  • Lung / metabolism
  • Lung / physiopathology
  • Molecular Targeted Therapy
  • Mucociliary Clearance / drug effects*
  • Mutation
  • Phenotype
  • Signal Transduction / drug effects


  • CFTR protein, human
  • Epithelial Sodium Channel Blockers
  • Epithelial Sodium Channels
  • Cystic Fibrosis Transmembrane Conductance Regulator