Dawn of a New Era in the Diagnosis and Treatment of Airway Mucus Dysfunction

In chronic obstructive pulmonary disease (COPD), mucus dysfunction arises from several mechanisms, including excess production due to inflammation, decreased elimination due to impaired ciliary clearance and reduced cough efficiency, and excessive concentration due to smoke-induced dysfunction of transepithelial anion transport resembling CF (6, 7). Diagnostically, work from the Severe Asthma Research Program funded by the NHLBI demonstrated mucus plugs by CT imaging in the airways of 58% of subjects with asthma but less than 5% of healthy controls (9). [...]the extent of mucus plugging correlated strongly with severity of airflow obstruction, higher asthma medication requirements, and worse asthma control. For further development of P3001 or other mucolytics, investigators will need to determine the optimal balance between achieving a sufficient reduction of disulfide bonds to diminish mucus viscoelasticity and avoiding an excessive reduction that might impair ciliary clearance or disrupt disulfides on nonmucin protein targets. Because P3001 affects disulfide bonding of both MUC5AC and MUC5B, a benefit of this mucolytic approach could be the ability to treat muco-obstructive diseases broadly, including asthma, where MUC5AC dominates, and CF, where MUC5B dominates. Acquired cystic fibrosis transmembrane conductance regulator dysfunction in chronic bronchitis and other diseases of mucus clearance.