Inhaled protein/peptide-based therapies for respiratory disease

Abstract

Asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are all chronic pulmonary diseases, albeit with different etiologies, that are characterized by airflow limitation, chronic inflammation, and abnormal mucus production/rheology. Small synthetic molecule-based therapies are commonly prescribed for all three diseases. However, there has been increased interest in "biologicals" to treat these diseases. Biologicals typically constitute protein- or peptide-based therapies and are often more potent than small molecule-based drugs. In this review, we shall describe the pros and cons of several different biological-based therapies for respiratory disease, including dornase alfa, a recombinant DNAase that reduces mucus viscosity and short palate lung and nasal epithelial clone 1 (SPLUNC1)-derived peptides that treat Na(+) hyperabsorption and rebalance CF airway surface liquid homeostasis.

Keywords: Aerosolization; Alpha-1-antitrypsin (AAT); BPIFA1; Biotherapies; CFTR; ENaC; Goblet cell metaplasia; Inflammation; Mucociliary clearance; Nebulization; Neutrophil elastase (NE); Omalizumab; PLUNC; Pulmozyme.

Fig. 1

Rationale for SPLUNC1-derived peptide therapy for CF lung disease. a In normal airways, bicarbonate secretion through CFTR maintains ASL pH at ~7.0. At this pH, secreted SPLUNC1 can bind to ENaC, leading to internalization and inhibition of the channel. This helps maintain airways hydration and mucus clearance. b In CF airways, the acidic ASL, caused by a lack of bicarbonate secretion through dysfunctional CFTR, causes SPLUNC1 to adopt an inappropriate conformation, where the ENaC inhibitory domain (also known as the S18 region) cannot bind to ENaC, leading to Na⁺ hyperabsorption and ASL dehydration. c S18-derived peptides are pH-independent and can inhibit ENaC to reduce Na⁺ absorption and help normalize airway hydration/mucus clearance in acidic CF airways