From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations

Abstract

More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.

Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product

“…Several lines of evidence suggest multiple defects in W1282X-CFTR and support corrector, potentiator, and readthough strategies (12). Transcript encoding W1282X-CFTR was seen in nasal epithelial cells of homozygous W1282X CF subjects with 30 -80% abundance compared with that of wild type CFTR in non-CF subjects (13).…”

Pharmacological Rescue of Conditionally Reprogrammed Cystic Fibrosis Bronchial Epithelial Cells

“…CFTR mutations are classified according to their disruptive mechanisms, and therapies targeting the underlying cause are directed by mutation class (2,3). The class III G551D CFTR mutation results in a properly localized but dysfunctional channel.…”

AJRCCM: 100-Year Anniversary.Progress along the Pathway of Discovery Leading to Treatment and Cure of Cystic Fibrosis

“…The mutation also reduced the channel's opening rate, indicating that one mutation could have multiple deleterious consequences. Indeed, later studies showed that the Phe508del mutation also reduced Phe508del lifetime at the cell membrane (37)(38)(39).…”

“…Other genetic variations (modifier genes), epigenetic modifications, and environmental exposures, including viral infections, can also determine the consequences of CFTR mutations in individuals. The availability of small molecules targeting CFTR is also providing an opportunity to identify mutations that respond to distinct chemicals (39,40).…”