Cystic fibrosis (CF) is a lethal monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that entails the (diagnostic) increase in sweat electrolyte concentrations, progressive lung disease with chronic inflammation and recurrent bacterial infections, pancreatic insufficiency, and male infertility. Therapies aimed at restoring the CFTR defect have emerged. Thus, a small molecule which facilitates chloride channel opening, the potentiator Ivacaftor, has been approved for the treatment of CF patients bearing a particular class of rare CFTR mutations. However, small molecules that directly target the most common misfolded CFTR mutant, F508del, and improve its intracellular trafficking in vitro, have been less effective than expected when tested in CF patients, even in combination with Ivacaftor. Thus, new strategies are required to circumvent the F508del-CFTR defect. Airway and intestinal epithelial cells from CF patients bearing the F508del-CFTR mutation exhibit an impressive derangement of cellular proteostasis, with oxidative stress, overactivation of the tissue transglutaminase (TG2), and disabled autophagy. Proteostasis regulators such as cysteamine can rescue and stabilize a functional F508del-CFTR protein through suppressing TG2 activation and restoring autophagy in vivo in F508del-CFTR homozygous mice, in vitro in CF patient-derived cell lines, ex vivo in freshly collected primary patient’s nasal cells, as well as in a pilot clinical trial involving homozygous F508del-CFTR patients. Here, we discuss how the therapeutic normalization of defective proteostasis can be harnessed for the treatment of CF patients with the F508del-CFTR mutation.

中文翻译：

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操纵蛋白质稳态修复囊性纤维化中的 F508del-CFTR 缺陷

囊性纤维化 (CF) 是一种致死的单基因疾病，由囊性纤维化跨膜电导调节剂 (CFTR) 基因突变引起，导致汗液电解质浓度增加（诊断性）、进行性肺部疾病伴慢性炎症和复发性细菌感染、胰腺功能不全、和男性不育。已经出现了旨在恢复 CFTR 缺陷的疗法。因此，一种促进氯通道开放的小分子，即增效剂 Ivacaftor，已被批准用于治疗携带特定类别的罕见 CFTR 突变的 CF 患者。然而，直接靶向最常见的错误折叠 CFTR 突变体 F508del 并在体外改善其细胞内运输的小分子，在 CF 患者中进行测试时，即使与 Ivacaftor 结合使用，效果也不如预期。因此，需要新的策略来规避 F508del-CFTR 缺陷。来自携带 F508del-CFTR 突变的 CF 患者的气道和肠上皮细胞表现出令人印象深刻的细胞蛋白质稳态紊乱，具有氧化应激、组织转谷氨酰胺酶 (TG2) 过度激活和自噬功能丧失。在 F508del-CFTR 纯合小鼠体内，在 CF 患者来源的细胞系中体外，在新鲜收集的原代患者鼻细胞中体外，蛋白稳态调节剂（如半胱胺）可以通过抑制 TG2 激活和恢复体内自噬来拯救和稳定功能性 F508del-CFTR 蛋白，以及在涉及纯合 F508del-CFTR 患者的试点临床试验中。这里，