PT - JOURNAL ARTICLE AU - Annalisa Addante AU - Wilfred Raymond AU - Irina Gitlin AU - Annabelle Charbit AU - Xavier Orain AU - Aaron Wolfe Scheffler AU - Aditi Kuppe AU - Julia Duerr AU - Maria Daniltchenko AU - Marika Drescher AU - Simon Y. Graeber AU - Anne-Marie Healy AU - Stefan Oscarson AU - John V. Fahy AU - Marcus A. Mall TI - A novel thiol-saccharide mucolytic for the treatment of muco-obstructive lung diseases AID - 10.1183/13993003.02022-2022 DP - 2023 May 01 TA - European Respiratory Journal PG - 2202022 VI - 61 IP - 5 4099 - http://erj.ersjournals.com/content/61/5/2202022.short 4100 - http://erj.ersjournals.com/content/61/5/2202022.full SO - Eur Respir J2023 May 01; 61 AB - Background Mucin disulfide cross-links mediate pathologic mucus formation in muco-obstructive lung diseases. MUC-031, a novel thiol-modified carbohydrate compound, cleaves disulfides to cause mucolysis. The aim of this study was to determine the mucolytic and therapeutic effects of MUC-031 in sputum from patients with cystic fibrosis (CF) and mice with muco-obstructive lung disease (βENaC-Tg mice).Methods We compared the mucolytic efficacy of MUC-031 and existing mucolytics (N-acetylcysteine (NAC) and recombinant human deoxyribonuclease I (rhDNase)) using rheology to measure the elastic modulus (G′) of CF sputum, and we tested effects of MUC-031 on airway mucus plugging, inflammation and survival in βENaC-Tg mice to determine its mucolytic efficacy in vivo.Results In CF sputum, compared to the effects of rhDNase and NAC, MUC-031 caused a larger decrease in sputum G′, was faster in decreasing sputum G′ by 50% and caused mucolysis of a larger proportion of sputum samples within 15 min of drug addition. Compared to vehicle control, three treatments with MUC-031 in 1 day in adult βENaC-Tg mice decreased airway mucus content (16.8±3.2 versus 7.5±1.2 nL·mm−2, p<0.01) and bronchoalveolar lavage cells (73 833±6930 versus 47 679±7736 cells·mL−1, p<0.05). Twice-daily treatment with MUC-031 for 2 weeks also caused decreases in these outcomes in adult and neonatal βENaC-Tg mice and reduced mortality from 37% in vehicle-treated βENaC-Tg neonates to 21% in those treated with MUC-031 (p<0.05).Conclusion MUC-031 is a potent and fast-acting mucolytic that decreases airway mucus plugging, lessens airway inflammation and improves survival in βENaC-Tg mice. These data provide rationale for human trials of MUC-031 in muco-obstructive lung diseases.MUC-031, a novel thiol-saccharide mucolytic drug, is potent and fast acting in rheology-based sputum assays and improves mucus obstruction, airway inflammation and survival in a mouse model of muco-obstructive lung disease http://bit.ly/3Z2UIVQ