Mucus-targeting therapies of defective mucus clearance for cystic fibrosis: A short review

Abstract

In the lungs, defective CFTR associated with cystic fibrosis (CF) represents the nidus for abnormal mucus clearance in the airways and consequently a progressive lung disease. Defective CFTR-mediated Cl^- secretion results in altered mucus properties, including concentration, viscoelasticity, and the ratio of the two mucins, MUC5B and MUC5AC. In the past decades, therapies targeting the CF mucus defect, directly or indirectly, have been developed; nevertheless, better treatments to prevent the disease progression are still needed. This review summarizes the existing knowledge on the defective mucus in CF disease and highlights it as a barrier to the development of future inhaled genetic therapies. The use of new mucus-targeting treatments is also discussed, focusing on their potential role to halt the progress of CF lung disease.

Figure 1:. Mucus transport in healthy airways vs. CF airways.

A) In healthy airways, a well-balanced activity of ions (Na⁺ and Cl⁻), water, and mucus, across the lung epithelium results in an efficient mucus transport: Here, a well-hydrated PCL layer ensures that cilia can efficiently sweep away mucus and noxious inhaled microorganisms, preventing their accumulation in the airways. B) In CF airways, defective CFTR (mainly expressed in secretory cells) leads to impaired fluid secretion activity in mucin-producing goblet cells, leading to ASL dehydration and a PCL and cilia collapse that fails to transport mucus and infectious particles out of the lungs. The result is mucus obstruction and chronic bacterial infection in the airways and progressive lung disease.