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

• Type of Material: Article
• Authors: Gudio Veit, McGill University; Radu G. Avramescu, McGill University; Annette N. Chiang, University of Pittsburgh; Scott A. Houck, University of North Carolina; Zhiwei Cai, University of Bristol; Kathryn W. Peters, University of Pittsburgh; Jeong S. Hong, University of Alabama, Birmingham; Harvey B. Pollard, Uniformed Services University of the Health Sciences; William B. Guggino, Johns Hopkins University; William E. Balch, Scripps Research Institute; William R. Skach, Oregon Health and Science University; Garry R. Cutting, Johns Hopkins University; Raymond A. Frizzell, University of Pittsburgh; David N. Sheppard, University of Bristol; Douglas M. Cyr, University of North Carolina; Eric Sorscher, Emory University; Jeffrey L. Brodsky, University of Pittsburgh; Gergely L. Lukacs, McGill University
• Language: English
• Date: 2016-02-01
• Publisher: American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Veit et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1091/mbc.E14-04-0935
• Title of Journal or Parent Work: Molecular Biology of the Cell
• ISSN: 1059-1524
• Volume: 27
• Issue: 3
• Start Page: 424
• End Page: 433
• Grant/Funding Information: R.G.A. was supported by CF Canada Studentship; G.L.L. is a recipient of a Canada Research Chair.; The work described here was supported by the following institutions and grants: National Institutes of Health (NIH) NO1-HL28187 and IAA-A-HL-14-007.001 to H.B.P.; Cystic Fibrosis Foundation (CFF), NIH DK51870, TRDRP23RT-0012, and HL095524 to W.E.B.; NIH R01 DK, CFF CUTT13A1, and CUTTXX0 to G.R.C.; CFFT SHEPPA14XX0 and Cystic Fibrosis Trust to D.N.S.; NIH R01-DK068196, P30-DK072506, and CFFT FRIZZE05X0 to R.A.F.; NIH RO1 GM56981 and CFFT CYR13XX0 to D.M.C.; the CFF Research Development Program, CFFT SORSCH05XXO, and SORSCH14XXO to E.J.S.; CFFT BRODSK13XX0 and NIH GM75061 to J.L.B.; CF Canada, CFFT Lukacs13XXO, NIH DK075302, and Canadian Institutes of Health Research to G.L.L.
• Keywords: Life Sciences & Biomedicine; CHANNEL FUNCTION; RANDOMIZED CONTROLLED-TRIAL; NUCLEOTIDE-BINDING DOMAIN; CONFORMATIONAL MATURATION; PLASMA-MEMBRANE; Science & Technology; NONSENSE MUTATIONS; MESSENGER-RNA; ENDOPLASMIC-RETICULUM; SOCIOECONOMIC-STATUS; Cell Biology; TRANSMEMBRANE CONDUCTANCE REGULATOR
• Research Categories: Biology, Physiology; Health Sciences, Pharmacology; Biology, Cell

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.