Abstract
The gene responsible for cystic fibrosis (CF) was discovered 25 years ago. This breakthrough has enabled a sophisticated understanding of how various mutations lead to specific alterations in the structure and function of the CF transmembrane regulator (CFTR) protein. Until recently, all therapies in CF were focused on ameliorating the downstream consequences of CFTR dysfunction. High-throughput drug screening approaches have yielded compounds that can modify CFTR structure and function, thus targeting the basic defect in CF. The present article describes the CFTR mutational classes, reviews mutation-specific therapies currently in late-phase clinical development, and highlights research opportunities and challenges with personalized medicine in CF.
Highlights
The gene responsible for cystic fibrosis (CF) was discovered 25 years ago
The discovery has enabled a sophisticated understanding of how various mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) lead to alterations in the structure and function of the resulting protein
Class III mutations are missense mutations but cause amino acid substitutions that result in Figure 1) Three targeted sites of action for oral cystic fibrosis transmembrane regulator (CFTR) modulators already approved or in late-phase clinical development for the treatment of cystic fibrosis
Summary
CFTR protein defect or ‘gating’ defect channel conductance protein synthesis membrane stability. The landscape of CF therapeutics changed dramatically with the recent approval of ivacaftor (Kalydeco, Vertex Pharmaceuticals Inc, USA), a small-molecule oral CFTR potentiator therapy that targets the defective CFTR protein in patients with a class III G551D mutation. VX-770, later known as ivacaftor, increased CFTR-mediated chloride transport up to 50% of wild-type levels in cell culture systems derived from patients with a G551D mutation It was evaluated in a pivotal phase III, 48-week placebo-controlled study involving patients ≥12 years of age with at least one copy of the G551D mutation [7]. Two near-identical phase III studies evaluating lumacaftor and ivacaftor in 1000 patients homozygous for the delta F508 mutation and ≥12 years of age has just been completed [15] Both studies met their primary end points, with a 3% to 4% absolute increase in FEV1 over a 24-week period compared with placebo. Our Pubmed search did not identify any agents in late phase clinical development targeting class V or VI mutations; there are gene-based therapies in the pipeline
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