Lumacaftor alone and combined with ivacaftor: preclinical and clinical trial experience of F508del CFTR correction

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.