SCIENCE@home

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

Ren-Jay Shei,Jacelyn Emily Peabody Lever,Niroop Kaza,S. Rowe

Published 2018 in Current opinion in pharmacology (Print)

ABSTRACT

HighlightsENaC contributes to airway surface liquid homeostasis in CF, though whether ENaC activity is abnormal in CF is unresolved.ENaC inhibitors are in development as CF therapeutics to restore airway surface liquid hydration.Use of ENaC as a therapeutic target in CF has yet to be successfully translated to CF patients.Some direct and indirect small molecule inhibitors have been unsuccessful due to off‐target effects and potential adverse events.New approaches with peptide analogs and molecular strategies which maximize efficacy and specificity are promising. &NA; Figure. No Caption available. 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 RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-100 of 105 references · Page 1 of 2

12
Next

CITED BY

Showing 1-69 of 69 citing papers · Page 1 of 1