Parion Sciences (United States)

<b>Introduction:</b> Primary ciliary dyskinesia (PCD) is a rare genetic disease with defective ciliary function leading to impaired mucociliary clearance, mucus hyperconcentration, airway inflammation, and lower respiratory tract infections, causing bronchiectasis and progressive lung function decline. There are no clinically proven therapies that improve mucociliary clearance or lung function in PCD. <b>Objective:</b> The objective of this Phase 2 trial was to evaluate the safety and efficacy of treatment with idrevloride, an epithelial sodium channel (ENaC) inhibitor, in adolescents and adults with PCD. The primary endpoint was absolute change in percent predicted FEV1 (ppFEV1) after 28 days, comparing idrevloride in hypertonic saline (HS) with HS. <b>Methods:</b> 123 people with PCD (pwPCD), age ≥12 years, at 32 sites in 10 countries, were randomized to idrevloride in HS and HS alone, or idrevloride alone and placebo in a 2:2:1:1 ratio in 2-treatment crossovers. Nebulised solutions were administered BID for 28 days in each treatment period. Spirometry was assessed before and after each period. <b>Results:</b> ppFEV1 improved from baseline following treatment with idrevloride in HS for 28 days compared with HS alone (difference between treatments=1.5%; p=0·044 [95% CI 0·04–3·0]). HS alone or idrevloride alone or placebo did not improve ppFEV1. No increase in serum potassium concentration or post-dose reduction in ppFEV1 was detected. Adverse events were typical of those seen in pwPCD and did not differ between treatment groups. <b>Conclusion:</b> Short-term inhaled idrevloride in HS was safe and effective for improving lung function in pwPCD. Longer studies are needed.

Although destructive airway disease is evident in young children with cystic fibrosis (CF), little is known about the nature of the early CF lung environment triggering the disease. To elucidate early CF pulmonary pathophysiology, we performed mucus, inflammation, metabolomic, and microbiome analyses on bronchoalveolar lavage fluid (BALF) from 46 preschool children with CF enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program and 16 non-CF disease controls. Total airway mucins were elevated in CF compared to non-CF BALF irrespective of infection, and higher densities of mucus flakes containing mucin 5B and mucin 5AC were observed in samples from CF patients. Total mucins and mucus flakes correlated with inflammation, hypoxia, and oxidative stress. Many CF BALFs appeared sterile by culture and molecular analyses, whereas other samples exhibiting bacterial taxa associated with the oral cavity. Children without computed tomography-defined structural lung disease exhibited elevated BALF mucus flakes and neutrophils, but little/no bacterial infection. Although CF mucus flakes appeared "permanent" because they did not dissolve in dilute BALF matrix, they could be solubilized by a previously unidentified reducing agent (P2062), but not N-acetylcysteine or deoxyribonuclease. These findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease and suggest that mucolytic and anti-inflammatory agents should be explored as preventive therapy.

Abstract The underlying defect in cystic fibrosis is mutation of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel expressed at the apical surface of lung epithelia. In addition to its export and maintenance at the cell surface, CFTR regulation involves repeated cycles of transport through the endosomal trafficking system, including endocytosis and recycling. Many of the known disease mutations cause CFTR intracellular trafficking defects that result in failure of ion channel delivery to the apical plasma membrane. Corrective maneuvers directed at improving transport to the plasma membrane are thwarted by rapid internalization and degradation of the mutant CFTR proteins. The molecular mechanisms involved in these processes are not completely understood but may involve protein-protein interactions with the C-terminal type I PDZ-binding motif of CFTR. Using a proteomic approach, we identify sorting nexin 27 (SNX27) as a novel CFTR binding partner in human airway epithelial Calu-3 cells. SNX27 and CFTR interact directly, with the SNX27 PDZ domain being both necessary and sufficient for this interaction. SNX27 co-localizes with internalized CFTR at sub-apical endosomal sites in polarized Calu-3 cells, and either knockdown of the endogenous SNX27, or over-expression of a dominant-negative SNX27 mutant, resulted in significant decreases in cell surface CFTR levels. CFTR internalization was not affected by SNX27 knockdown, but defects were observed in the recycling arm of CFTR trafficking through the endosomal system. Furthermore, knockdown of SNX27 in Calu-3 cells resulted in significant decreases in CFTR protein levels, consistent with degradation of the internalized pool. These data identify SNX27 as a physiologically significant regulator of CFTR trafficking and homeostasis in epithelial cells.