Lumacaftor alone and combined with ivacaftor: preclinical and clinical trial experience of F508del CFTR correction
Lumacaftor alone and combined with ivacaftor: preclinical and clinical trial experience of F508del CFTR correction
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DOI：
10.1586/17476348.2016.1122527
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发表时间：
2016-01-02
影响因子：
3.9
通讯作者：
Clancy, John P.
中科院分区：
文献类型：
--
作者：
Brewington, John J.;McPhail, Gary L.;Clancy, John P.
囊性纤维化（CF）是由编码囊性纤维化跨膜传导调节蛋白（CFTR）的基因突变引起的常染色体隐性疾病，导致显著的发病率和死亡率。CFTR是上皮细胞膜上的氯离子和碳酸氢根通道。最常见的CFTR突变是F508 del，导致质膜上的CFTR最小。目前的疾病管理是支持性的，而最终目标是开发恢复CFTR活性的疗法。我们总结了Lumacaftor的经验，Lumacaftor是一种增加质膜F508 del-CFTR水平的小分子。鲁玛卡托与依伐卡托（CFTR门控缺陷的调节剂）联合使用可改善F508 del突变纯合子患者的临床结局指标。鲁玛卡托代表了CF生化异常治疗的重大进展。CFTR调节剂的进一步开发将改善目前的治疗方法，尽管目前尚不清楚这种方法是否会为所有CFTR突变提供治疗。
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR), leading to significant morbidity and mortality. CFTR is a chloride and bicarbonate channel at the epithelial cell membrane. The most common CFTR mutation is F508del, resulting in minimal CFTR at the plasma membrane. Current disease management is supportive, whereas an ultimate goal is to develop therapies to restore CFTR activity. We summarize experience with lumacaftor, a small molecule that increases F508del-CFTR levels at the plasma membrane. Lumacaftor in combination with ivacaftor, a modulator of CFTR gating defects, improves clinical outcome measures in patients homozygous for the F508del mutation. Lumacaftor represents a significant advancement in the treatment of biochemical abnormalities in CF. Further development of CFTR modulators will improve upon current therapies, although it remains unclear whether this approach will provide therapies for all CFTR mutations.