WS05.05SPL5AC， MUC5AC降低囊性纤维化和其他粘膜阻塞性疾病的ASO

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis Pub Date : 2025-06-01 DOI:10.1016/j.jcf.2025.03.520

E. Ozeri-Galai , Y.S. Oren , C.D. Stampfer , R.M. Elgrabli , T. Blinder , T. Mordechai , S.A. Jubeh , B. Kerem , G. Hart

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引用次数: 0

摘要

气道粘液是抵抗病原体和毒素的第一道防线。气道粘液的主要成分是粘蛋白MUC5AC和MUC5B。在CF中，CFTR通道活性缺陷导致粘液脱水和粘蛋白含量增加。在粘膜梗阻性疾病中，如CF、哮喘、COPD、NCFB等，由于杯状细胞增生导致粘蛋白过表达，MUC5AC / MUC5B比值升高，引起黏液粘稠、气道阻塞、慢性感染和炎症。Splisense正在开发一种反义寡核苷酸（ASO）药物，旨在降低CF和其他粘膜阻塞性疾病（哮喘、COPD和NCFB）患者的MUC5AC水平，促进有效的粘液清除，缓解呼吸阻塞和炎症。方法筛选采用专有算法设计和优化的splisense ASOs，并利用RT-qPCR和Western Blot分析高效候选先导ASOs在IL-13诱导的原代HBEs中的作用。在工业标准疾病小鼠模型中进一步分析了主要候选物。结果发现SPL5AC临床候选物ASO高效，可通过黏液层有效递送至il -13诱导的HBEs，导致MUC5AC RNA和蛋白水平显著降低。在粘膜阻塞性疾病小鼠模型的体内研究表明，SPL5AC降低了Muc5ac水平，从而改善了粘膜阻塞性疾病的典型临床特征。其中包括粘液塞减少、杯状细胞增生和免疫反应减弱。初步的毒理研究表明SPL5AC具有良好的安全性。结论在CF等黏液阻塞性疾病患者中恢复适当的黏液粘弹性和清除率仍然是一个主要目标。我们的研究结果表明，SPL5AC ASO对CF和其他粘膜阻塞性患者具有潜在的治疗益处，目标是在2025年推进到人类首次。

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WS05.05SPL5AC, MUC5AC Lowering ASO for cystic fibrosis and other muco-obstructive diseases

Background

Airway mucus functions as the first line of defense against pathogens and toxins. The major components of the airway mucus are the mucins, MUC5AC and MUC5B. In CF, defective CFTR channel activity leads to dehydrated mucus and increased mucin content. In muco-obstructive diseases, such as CF, asthma, COPD, and NCFB, mucins are overexpressed due to goblet cell hyperplasia and the ratio of MUC5AC to MUC5B is elevated, causing thick mucus, airway obstruction, and chronic infections and inflammation. Splisense is developing an antisense oligonucleotide (ASO) drug aiming to reduce MUC5AC levels in patients with CF and other muco-obstructive diseases (Asthma, COPD and NCFB), facilitating efficient mucus clearance and alleviating respiratory blockage and inflammation.

Methods

Splisense ASOs designed and optimized using a proprietary algorithm were screened and the effect of highly potent lead candidate ASOs was further analyzed in IL-13 induced primary HBEs using RT-qPCR and Western Blot. The lead candidate was further analyzed in industry standard disease mouse models.

Results

The SPL5AC clinical candidate ASO was found to be highly potent and effectively delivered through the mucus layer to IL-13-induced HBEs, leading to a significant reduction in MUC5AC RNA and protein levels. In vivo studies in muco-obstructive disease mouse models demonstrated that SPL5AC reduced Muc5ac levels, resulting in improved clinical features typical of muco-obstructive diseases. These included a reduction in mucus plugs, goblet cell hyperplasia, and an attenuated immune response. Initial tox studies indicate the promising safety profile of SPL5AC.

Conclusions

Restoring proper mucus viscoelasticity and clearance in the lungs of patients with muco-obstructive diseases like CF, remains a major goal. Our results demonstrate that SPL5AC ASO has a potential therapeutic benefit for CF and other muco-obstructive patients with the objective to advance to first in Human in 2025.

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来源期刊

Journal of Cystic Fibrosis 医学-呼吸系统

CiteScore

10.10

自引率

13.50%

发文量

1361

审稿时长

50 days

期刊介绍： The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.