Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770
Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770
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DOI：
10.1073/pnas.0904709106
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发表时间：
2009-11-03
影响因子：
11.1
通讯作者：
Negulescu, Paul
中科院分区：
文献类型：
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作者：
Van Goor, Fredrick;Hadida, Sabine;Negulescu, Paul
囊性纤维化（CF）是一种致命的遗传性疾病，由编码CF跨膜传导调节因子（CFTR）的基因突变引起，CFTR是一种蛋白激酶A（PKA）激活的上皮阴离子通道，参与包括肺在内的多个器官中的盐和液体转运。大多数CF突变要么减少细胞表面CFTR通道的数量（例如，例如，在一个实施例中，合成或加工突变）或损害通道功能（例如，例如，在一个实施例中，门控或电导突变）或两者。目前还没有针对CFTR的获批疗法。在这里，我们描述了VX-770的体外药理学，VX-770是一种口服生物可利用的CFTR增效剂，临床开发用于治疗CF。在重组细胞中，VX-770在F508 del加工突变和G551 D门控突变中均增加CFTR通道开放概率（P-o）。VX-770还使一个等位基因携带G551 D门控突变和另一个等位基因携带F508 del加工突变的培养人CF支气管上皮细胞（HBE）中的Cl-分泌增加约10倍，达到从无CF个体中分离的HBE中观察到的Cl-分泌的约50%。此外，VX-770减少了过多的Na+和液体吸收，以防止顶端表面脱水和增加这些上皮培养物中的纤毛跳动。这些结果支持恢复或增加CFTR功能的药理学试剂可以拯救人CF气道中的上皮细胞功能的假设。
Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung. Most CF mutations either reduce the number of CFTR channels at the cell surface (e. g., synthesis or processing mutations) or impair channel function (e. g., gating or conductance mutations) or both. There are currently no approved therapies that target CFTR. Here we describe the in vitro pharmacology of VX-770, an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (P-o) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl- secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by approximate to 10-fold, to approximate to 50% of that observed in HBE isolated from individuals without CF. Furthermore, VX-770 reduced excessive Na+ and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures. These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway.