Farinha Carlos M, Matos Paulo
BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Portugal.
Department of Human Genetics, National Health Institute 'Dr. Ricardo Jorge', Lisboa, Portugal.
FEBS J. 2016 Jan;283(2):246-64. doi: 10.1111/febs.13531. Epub 2015 Oct 18.
Cystic fibrosis has attracted much attention in recent years due to significant advances in the pharmacological targeting of the basic defect underlying this recessive disorder: the deficient functional expression of mutant cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels at the apical membrane of epithelial cells. However, increasing evidence points to the reduced efficacy of single treatments, thus reinforcing the need to combine several therapeutic strategies to effectively target the multiple basic defect(s). Protein-repair therapies that use potentiators (activating membrane-located CFTR) or correctors (promoting the relocation of intracellular-retained trafficking mutants of CFTR) in frequent mutations such as F508del and G551D have been put forward and made their way to the clinic with moderate to good efficiency. However, alternative (or additional) approaches targeting the membrane stability of mutant proteins, or correcting the cellular phenotype through a direct effect upon other ion channels (affecting the overall electrolyte transport or simply promoting alternative chloride transport) or targeting less frequent mutations (splicing variants, for example), have been proposed and tested in the field of cystic fibrosis (CF). Here, we cover the different strategies that rely on novel findings concerning the CFTR interactome and signalosome through which it might be possible to further influence the cellular trafficking and post-translational modification machinery (to increase rescued CFTR abundance and membrane stability). We also highlight the new data on strategies aiming at the regulation of sodium absorption or to increase chloride transport through alternative channels. The development and implementation of these complementary approaches will pave the way to combinatorial therapeutic strategies with increased benefit to CF patients.
近年来，囊性纤维化引起了广泛关注，这是因为针对这种隐性疾病潜在基本缺陷的药物靶向治疗取得了重大进展：上皮细胞顶端膜上突变型囊性纤维化跨膜电导调节因子（CFTR）氯离子通道的功能表达不足。然而，越来越多的证据表明单一治疗的疗效降低，因此更有必要联合多种治疗策略来有效针对多种基本缺陷。针对常见突变如F508del和G551D，已提出使用增强剂（激活位于膜上的CFTR）或校正剂（促进细胞内滞留的CFTR转运突变体重新定位）的蛋白质修复疗法，并已以中等至良好的效率进入临床。然而，已经提出并在囊性纤维化（CF）领域进行了测试的替代（或附加）方法包括：针对突变蛋白的膜稳定性，或通过直接作用于其他离子通道（影响整体电解质转运或简单促进替代氯离子转运）来校正细胞表型，或针对较少见的突变（例如剪接变体）。在这里，我们介绍了基于CFTR相互作用组和信号体新发现的不同策略，通过这些策略可能进一步影响细胞转运和翻译后修饰机制（以增加挽救的CFTR丰度和膜稳定性）。我们还强调了旨在调节钠吸收或通过替代通道增加氯转运的策略的新数据。这些互补方法的开发和实施将为对CF患者更有益的联合治疗策略铺平道路。
