Laselva Onofrio, Guerra Lorenzo, Castellani Stefano, Favia Maria, Di Gioia Sante, Conese Massimo
Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
Pulm Pharmacol Ther. 2022 Feb;72:102098. doi: 10.1016/j.pupt.2021.102098. Epub 2021 Nov 15.
The cystic fibrosis (CF) lung disease is due to the lack/dysfunction of the CF Transmembrane Conductance Regulator (CFTR), a chloride channel expressed by epithelial cells as the main regulator of ion and fluid homeostasis. More than 2000 genetic variation in the CFTR gene are known, among which those with identified pathomechanism have been divided into six mutation classes. A major advancement in the pharmacotherapy of CF has been the development of small-molecule drugs hitting the root of the disease, i.e. the altered ion and fluid transport through the airway epithelium. These drugs, called CFTR modulators, have been advanced to the clinics to treat nearly 90% of CF patients, including the CFTR potentiator ivacaftor, approved for residual function mutations (Classes III and IV), and combinations of correctors (lumacaftor, tezacaftor, elexacaftor) and ivacaftor for patients bearing at least one the F508del mutation, the most frequent mutation belonging to class II. To cover the 10% of CF patients without etiological therapies, other novel small-molecule CFTR modulators are in evaluation of their effectiveness in all the CFTR mutation classes: read-through agents for Class I, correctors, potentiators and amplifiers from different companies for Class II-V, stabilizers for Class VI. In alternative, other solute carriers, such as SLC26A9 and SLC6A14, are the focus of intensive investigation. Finally, other molecular targets are being evaluated for patients with no approved CFTR modulator therapy or as means of enhancing CFTR modulatory therapy, including small molecules forming ion channels, inhibitors of the ENaC sodium channel and potentiators of the calcium-activated chloride channel TMEM16A. This paper aims to give an up-to-date overview of old and novel CFTR modulators as well as of novel strategies based on small-molecule drugs. Further investigations in in-vivo and cell-based models as well as carrying out large prospective studies will be required to determine if novel CFTR modulators, stabilizers, amplifiers, and the ENaC inhibitors or TMEM16A potentiators will further improve the clinical outcomes in CF management.
囊性纤维化（CF）肺部疾病是由于CF跨膜传导调节因子（CFTR）缺乏或功能异常所致。CFTR是一种由上皮细胞表达的氯离子通道，是离子和液体稳态的主要调节因子。已知CFTR基因存在2000多种基因变异，其中已明确致病机制的变异被分为六个突变类别。CF药物治疗的一项重大进展是开发出了针对疾病根源的小分子药物，即通过气道上皮改变离子和液体转运。这些药物被称为CFTR调节剂，已进入临床用于治疗近90%的CF患者，包括被批准用于残余功能突变（III类和IV类）的CFTR增强剂依伐卡托，以及用于至少携带一种F508del突变（最常见的II类突变）患者的校正剂（鲁马卡托、替扎卡托、依列卡托）与依伐卡托的组合。为了覆盖10%没有病因疗法的CF患者，其他新型小分子CFTR调节剂正在评估其对所有CFTR突变类别的有效性：I类的通读剂、不同公司针对II - V类的校正剂、增强剂和放大器、VI类的稳定剂。另外，其他溶质载体，如SLC26A9和SLC6A14，是深入研究的重点。最后，正在评估其他分子靶点，用于没有获批CFTR调节剂治疗的患者或作为增强CFTR调节治疗的手段，包括形成离子通道的小分子、ENaC钠通道抑制剂和钙激活氯离子通道TMEM16A增强剂。本文旨在对新旧CFTR调节剂以及基于小分子药物的新策略进行最新概述。需要在体内和细胞模型中进行进一步研究以及开展大型前瞻性研究，以确定新型CFTR调节剂、稳定剂、放大器以及ENaC抑制剂或TMEM16A增强剂是否会进一步改善CF治疗的临床结果。
