一种用于治疗粘液阻塞性肺病的新型硫醇糖粘液溶解剂,European Respiratory Journal

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一种用于治疗粘液阻塞性肺病的新型硫醇糖粘液溶解剂
European Respiratory Journal ( IF 16.6 ) Pub Date : 2023-05-25 , 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 _{2,

5,

9,

10}

Affiliation

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.
German Centre for Lung Research (DZL), associated partner, Berlin, Germany.
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, Berlin, Germany.
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland.
Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Ireland.
Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA.
J.V. Fahy and M.A. Mall contributed equally as senior authors.
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

背景

粘蛋白二硫化物交联介导粘液阻塞性肺部疾病中的病理性粘液形成。MUC-031 是一种新型硫醇修饰碳水化合物化合物，可裂解二硫化物以引起粘液溶解。本研究的目的是确定 MUC-031 对囊性纤维化 (CF) 患者和粘液阻塞性肺病小鼠（βENaC-Tg 小鼠）痰液的粘液溶解和治疗作用。

方法

我们使用流变学测量 CF 痰的弹性模量 (G')，比较了 MUC-031 和现有粘液溶解剂（N-乙酰半胱氨酸 (NAC) 和重组人脱氧核糖核酸酶 I (rhDNase)）的粘液溶解功效，并测试了 MUC-031 的效果。 031 对 βENaC-Tg 小鼠气道粘液堵塞、炎症和存活的影响，以确定其体内粘液溶解功效。

结果

在 CF 痰中，与 rhDNase 和 NAC 的作用相比，MUC-031 引起痰 G' 的降低幅度更大，使痰 G' 降低 50% 的速度更快，并在用药 15 分钟内引起较大比例痰样本的粘液溶解添加。与载体对照相比，成年 βENaC-Tg 小鼠在 1 天内接受 3 次 MUC-031 治疗可降低气道粘液含量（16.8±3.2对比7.5±1.2 nL·mm ^–2，p<0.01）和支气管肺泡灌洗细胞（73 833± 6930与47 679±7736 个细胞·mL ^–1，p<0.05）。连续两周每天两次 MUC-031 治疗也导致成年和新生 βENaC-Tg 小鼠的这些结果下降，并将死亡率从用媒介物治疗的 βENaC-Tg 新生儿的 37% 降低到用 MUC-031 治疗的 21%（ p<0.05）。

结论

MUC-031 是一种有效且快速起效的粘液溶解剂，可减少气道粘液堵塞、减轻气道炎症并提高 βENaC-Tg 小鼠的存活率。这些数据为 MUC-031 治疗粘液阻塞性肺病的人体试验提供了理论依据。

"点击查看英文标题和摘要"

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

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.

更新日期：2023-05-25

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