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

https://doi.org/10.1016/j.coph.2022.102248Get rights and content

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.

Section snippets

Mucus transport in normal airways vs. CF airways

Cystic fibrosis (CF) is characterized by impaired transport of chloride and bicarbonate across the cystic fibrosis transmembrane regulator (CFTR) channel, which results, in the airways, in a critical disease-initiating step: a reduction of mucus transport and clearance [1, 2, 3].

In normal airways, an effective mucus transport and clearance requires a well-hydrated airway surface layer (ASL), composed of a mucus layer and a periciliary layer (PCL), which acts as a lubricating layer in which the

CF mucus defect

The healthy mucus layer that covers the human airways is a complex mixture of many components, such as mucins, globular proteins, DNA, ions, cells, antimicrobial peptides, salts, and water [18,19]. The interdependency of these components is most apparent in CF airways, where the ion-mediated changes in mucus concentration have a tremendously adverse effect on its overall biophysical properties [6,20]. Here, we explored mucus properties primarily affected by CF: concentration, viscoelasticity,

DNAse

As mentioned above, increased DNA released from neutrophils in CF is associated with a higher viscoelasticity. Therefore, an inhaled form of a recombinant human DNAse enzyme that selectively hydrolyzes DNA, named Dornase Alfa, was developed for inhaled delivery. This drug was one of the first approved to treat CF in 1993 and is still commonly used by most patients in their CF management [42,43].

As expected, hydrolyzing DNA with Dornase Alfa is capable at decreasing the viscoelasticity of CF

Reducing agents/mucolytics

As mentioned above, CF sputum has higher oxidative stress due to airway inflammation which generates mucin cross-link via multiple intermolecular disulfide bonds. Therefore, researchers have pursued the development of disulfide bond reducing agents as a mucolytic therapy for many decades [27,48].

In the 1960s, Mucomyst (N-acetylcysteine [NAC]) started being used to treat CF; however, later clinical research demonstrated a limited effect of this drug in addition to adverse effects, such as

Conclusion

This review highlights that the abnormal mucus in CF airways is a key pathological factor, which is already observed in the early stages of CF lung disease. Therefore, studies on mucus cell biology, production, and biophysical properties in normal and CF airways are essential. Furthermore, this knowledge is promising for developing novel approaches in genetic therapy, small molecule inhibition of signaling pathways, CFTR modulation, and mucolytics. Therefore, tackling the mucus defects in CF is

Funding

This work was supported by National Institutes of Health grants R01HL125280 and P30DK065988; and by Cystic Fibrosis Foundation grants FIGUEI18F0; BUTTON19G0; RIBEIR18G0; RIBEIR20P0 and BOUCHE19R0.

Conflict of interest statement

Nothing declared.

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