A novel thiol-saccharide mucolytic for the treatment of muco-obstructive lung diseases

  • Eur Respir J. 2023 May 25;61(5):2202022. doi: 10.1183/13993003.02022-2022.
Annalisa Addante  1  2 ,  Wilfred Raymond  3 ,  Irina Gitlin  3 ,  Annabelle Charbit  3 ,  Xavier Orain  3 ,  Aaron Wolfe Scheffler  4 ,  Aditi Kuppe  1  2 ,  Julia Duerr  1  2 ,  Maria Daniltchenko  1 ,  Marika Drescher  1 ,  Simon Y Graeber  1  2  5 ,  Anne-Marie Healy  6 ,  Stefan Oscarson  7 ,  John V Fahy  3  8  9 ,  Marcus A Mall  10  2  5  9
Affiliations
  • 1. Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 2. German Centre for Lung Research (DZL), associated partner, Berlin, Germany.
  • 3. Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
  • 4. Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
  • 5. Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • 6. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland.
  • 7. Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Ireland.
  • 8. Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA.
  • 9. J.V. Fahy and M.A. Mall contributed equally as senior authors.
  • 10. Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany [email protected].
PMID: 37080569 DOI: 10.1183/13993003.02022-2022
Abstract

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.

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