Small Molecules that Rescue F508del CFTR as Cystic Fibrosis Therapies

Abstract

Cystic fibrosis (CF) is an orphan disease caused by mutations in CFTR, an epithelial ion channel. While CF is a multi-organ disorder, the primary cause of morbidity and mortality is lung disease. The F508del mutation, present in around 90% of patients, causes complex defects in folding, channel gating, endocytosis and thermal stability. The folding and gating defects can be addressed by small-molecule corrector and potentiator compounds, respectively. Combinations composed of a single corrector and a potentiator have shown positive responses in patients with the F508del mutation in ongoing clinical trials. Experiments in patient-derived airway epithelia suggest that a combination therapy of two correctors and a potentiator may provide greater efficacy. Advancement of corrector compounds has been significantly enabled by measurements of efficacy and potency in patient-derived primary airway epithelial cells. The development of biomarkers that bridge between in vitro assays and clinical responses and ‘probe’ compounds to assist in the identification of corrector targets would further empower the field. The discovery and development of CFTR modulator drugs has been accelerated by the Cystic Fibrosis Foundation, which has funded research in academia and industry and facilitated clinical trials. Because of the synergy between patient advocacy, academic research and pharmaceutical industry work, the prospect of a pharmacological therapy that addresses the root cause of disease has never been closer for most CF patients.