Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are the first approved drugs targeting underlying epithelial ion/fluid transport defects in patients with cystic fibrosis (CF). Current CFTR modulators restore mutant CFTR activity to up to ∼50% of normal CFTR Cl− channel function, translating into improvements in percentage predicted FEV1 and other clinical outcomes. In addition, reductions in airway bacterial colonisation are observed; however, patients fail to eradicate bacteria over time and still experience pulmonary exacerbations, and long-term safety of CFTR modulator therapy remains unknown. Currently approved CFTR modulators are predicted to be effective for up to 90% of patients. A mutation-agnostic approach could address the remaining 10% with CFTR mutations unresponsive to CFTR modulator therapy and may act together with CFTR modulator therapy to further improve epithelial ion/fluid transport and clinical outcomes. Together with CFTR and other Cl− channels, the epithelial Na+ channel (ENaC) is key to regulating airway surface liquid homeostasis. ENaC activity is limiting for Na+/fluid absorption and remains intact or may even be increased in CF airways, leading to increased Na+/fluid absorption, airway surface dehydration, impaired mucociliary clearance, bacterial infection, inflammation and progressive lung damage – the major cause of CF-related morbidity and mortality. Inhibition of ENaC in the airways is therefore an attractive therapeutic target to counteract airway surface dehydration and downstream consequences in CF lung disease. This review examines ENaC inhibition in CF therapy, and describes a new ENaC inhibitor with potential mutation-agnostic therapeutic benefit, both alone, and in synergy with CFTR modulators.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Mall reports grants from German Federal Ministry of Education and Research , grants from German Research Foundation, grants from Einstein Foundation Berlin, during the conduct of the study; personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Polyphor, personal fees from Arrowhead Pharmaceuticals, personal fees from ProQR Therapeutics, personal fees from Spyryx Biosciences, personal fees from Vertex Pharmaceuticals, personal fees from Santhera, personal fees from Galapagos, personal fees from Sterna Biologicals, personal fees from Enterprise Therapeutics, personal fees from Celtaxys, outside the submitted work; In addition, Dr. Mall has a patent on the Scnn1b-transgenic mouse with royalties paid, and a patent on use of sodium channel blockers for early therapy of obstructive lung diseases issued.
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- Received March 31, 2020.
- Accepted July 18, 2020.
- Copyright ©ERS 2020