Cystic Fibrosis (CF) is an autosomal recessive disorder affecting ~70,000 patients worldwide. CF is caused by defects in the cystic fibrosis conductance transmembrane regulator (CFTR) protein that result from mutations in the <i>CFTR</i> gene. Defects in the CFTR protein lead to reduced chloride transport resulting in thick, sticky mucus that causes abnormalities in multiple organs. In the lungs, this excess mucus can lead to progressive loss of lung function and premature death. Several high throughput screening campaigns were performed to identify CFTR modulator hits that are able to increase CFTR function resulting in enhanced chloride transport. Extensive optimization efforts eventually resulted in the identification of two CFTR modulator drugs. Ivacaftor, a CFTR potentiator, increases CFTR channel gating while lumacaftor, known as a CFTR corrector, increases processing and trafficking of mutant CFTR to the cell surface. The two agents can be used in a combo therapy for patients who are homozygous for the most prevalent CFTR mutation, <i>F508del-CFTR</i>. A perspective will be provided on the discovery and development of CFTR modulators for the treatment of CF.

Targeting the cause of cystic fibrosis: Recent progress

255th National Meeting (2018)

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