CFTR Biomarker Centre and Translational CF Research Group Christiane Herzog Cystic Fibrosis Centre, Paediatric Pulmonology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Eur Respir Rev. 2013 Mar 1;22(127):58-65. doi: 10.1183/09059180.00008412.
Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.
囊性纤维化（CF）是由影响囊性纤维化跨膜电导调节因子（CFTR）蛋白的基因突变引起的。这些突变会影响 CFTR 蛋白的合成和向上皮细胞顶膜的转运，以及影响氯离子和碳酸氢根离子通过通道的门控或电导。CFTR 功能障碍导致几个器官系统（如胰腺、胃肠道、肝脏和呼吸系统）的上皮分泌物离子失衡。自 1989 年发现 CFTR 基因以来，研究一直集中在针对潜在的遗传缺陷上，以确定 CF 的治疗方法。研究的管理策略包括基因治疗和开发针对 CFTR 突变的小分子，称为 CFTR 调节剂。CFTR 调节剂通常通过高通量筛选测定法进行鉴定，然后使用细胞培养系统进行临床前验证。最近，一种这样的调节剂，即 CFTR 增效剂 ivacaftor，被批准作为 G551D-CFTR 突变的 CF 患者的口服治疗药物。Ivacaftor 的临床开发不仅代表了 CF 治疗的突破，也是个性化医学的一个值得注意的例子。
