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

Gudio Veit, Radu G. Avramescu, Annette N. Chiang, Scott A. Houck, Zhiwei Cai, Kathryn W. Peters, Jeong S. Hong, Harvey B. Pollard, William B. Guggino, William E. Balch, William R. Skach, Garry R. Cutting, Raymond A. Frizzell, David Sheppard, Douglas M. Cyr, Eric J. Sorscher, Jeffrey L. Brodsky, Gergely L. Lukacs

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.
Original languageEnglish
Pages (from-to)424-433
Number of pages10
JournalMolecular Biology of the Cell
Issue number3
Publication statusPublished - 1 Feb 2016


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