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

Molecular Biology of the Cell
Gudio VeitGergely L Lukacs

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 cau...Continue Reading

References

Jan 1, 1993·Annual Review of Physiology·J R Riordan
Jan 1, 1995·Annual Review of Genetics·J Zielenski, L C Tsui
Apr 25, 2000·Respiration; International Review of Thoracic Diseases·J Zielenski
May 24, 2001·American Journal of Respiratory and Critical Care Medicine·M S SchechterS C Fitzsimmons
Aug 21, 2001·Molecular Cell·R TarranR C Boucher
Feb 28, 2003·Lancet·Felix Ratjen, Gerd Döring
Jul 2, 2003·The Journal of Biological Chemistry·Hong YangA S Verkman
Feb 4, 2005·Nature Structural & Molecular Biology·Douglas M Cyr
May 13, 2005·The New England Journal of Medicine·Steven M RoweEric J Sorscher
Jan 16, 2007·Annual Review of Medicine·Richard C Boucher
Mar 14, 2007·The Journal of General Physiology·Silvia G BompadreTzyh-Chang Hwang
Apr 24, 2007·Nature·Ellen M WelchH Lee Sweeney
Feb 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Ming DuDavid M Bedwell
Apr 30, 2008·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Philip M Farrell
May 24, 2008·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Alfredo ViscaValerie M Hudson
Sep 25, 2008·Current Opinion in Pulmonary Medicine·Joseph M Collaco, Garry R Cutting
Jan 30, 2009·Molecular Biology of the Cell·Kai Du, Gergely L Lukacs
Oct 23, 2009·Proceedings of the National Academy of Sciences of the United States of America·Fredrick Van GoorPaul Negulescu
Dec 8, 2009·Nature Chemical Biology·Darren M HuttWilliam E Balch
Jan 8, 2010·American Journal of Physiology. Cell Physiology·Nicoletta PedemonteLuis J V Galietta
Jul 3, 2010·Science·Tsukasa OkiyonedaGergely L Lukacs
Jul 14, 2010·American Journal of Respiratory and Critical Care Medicine·Isabelle Sermet-GaudelusLangdon L Miller
Nov 19, 2010·The New England Journal of Medicine·Frank J AccursoBonnie W Ramsey
Nov 26, 2010·Angewandte Chemie·Patrick R CushingDean R Madden
Dec 24, 2010·Annals of the New York Academy of Sciences·Garry R Cutting
Jan 15, 2011·The European Respiratory Journal·M WilschanskiE Kerem
Mar 24, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Nico DerichsA S Verkman
Mar 29, 2011·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Ying-Chun YuYoshiro Sohma

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Citations

Apr 14, 2016·Pediatric Pulmonology·Edith T ZemanickCharles R Esther
Aug 3, 2016·Expert Review of Precision Medicine and Drug Development·Deborah M CholonMartina Gentzsch
Jul 7, 2016·Mediators of Inflammation·Andrea SchnúrGuido Veit
Jul 2, 2016·Science·David BalchinF Ulrich Hartl
Sep 23, 2016·Frontiers in Pharmacology·Miquéias Lopes-Pacheco
Oct 6, 2016·Cellular and Molecular Life Sciences : CMLS·Olga Zegarra-Moran, Luis J V Galietta
Oct 9, 2016·Cellular and Molecular Life Sciences : CMLS·Isabelle CallebautJean-Paul Mornon
Dec 17, 2016·American Journal of Respiratory Cell and Molecular Biology·Martina GentzschScott H Randell
Apr 6, 2017·SLAS Technology·Feng LiangMartin Mense
Sep 5, 2017·International Journal of Molecular Sciences·Weiqiang ZhangAnjaparavanda P Naren
Jan 20, 2018·American Journal of Physiology. Lung Cellular and Molecular Physiology·Marta StolarczykBob J Scholte
Jan 20, 2018·American Journal of Physiology. Lung Cellular and Molecular Physiology·Misak HarutyunyanAnjaparavanda P Naren
Mar 28, 2018·Expert Review of Respiratory Medicine·Anne BergougnouxCaroline Raynal
Mar 15, 2018·Current Opinion in Pediatrics·Elizabeth B Burgener, Richard B Moss
Jul 13, 2016·American Journal of Physiology. Lung Cellular and Molecular Physiology·Martina GentzschDouglas M Cyr
Sep 10, 2017·Physiological Genomics·Amy L PasternakDaniel L Hertz
Feb 15, 2018·Physiological Reviews·Ya-Xiong Tao, P Michael Conn
Oct 29, 2017·The Journal of General Physiology·Han-I YehTzyh-Chang Hwang
Aug 18, 2017·United European Gastroenterology Journal·Meike HohwielerAlexander Kleger
Aug 1, 2018·Pediatric Pulmonology·Bette S Pollard, Harvey B Pollard
Nov 22, 2017·Nucleic Acid Therapeutics·Shruti Sasaki, Shuling Guo
Feb 9, 2018·Cell Death and Differentiation·Amelia J BrennanIlia Voskoboinik
May 2, 2018·Annual Review of Genomics and Human Genetics·Wanda K O'Neal, Michael R Knowles
Aug 21, 2018·Current Opinion in Pulmonary Medicine·Kathryn J Crawford, Damian G Downey
Aug 24, 2018·American Journal of Physiology. Lung Cellular and Molecular Physiology·Yiting WangDavid N Sheppard
Dec 19, 2018·Pediatric Pulmonology·Donatello SalvatoreFabio Majo
Feb 13, 2019·Human Molecular Genetics·Frédéric AnglèsWilliam E Balch
Feb 10, 2019·Biological Chemistry·Xin MengRobert C Ford
Oct 6, 2018·The European Respiratory Journal·Martina GentzschCarla M P Ribeiro
Oct 19, 2017·Journal of the American Society of Nephrology : JASN·Emilie Cornec-Le GallPeter C Harris
Feb 15, 2019·Minerva pediatrica·Valeria R VillellaLuigi Maiuri
Jun 6, 2019·Nature Reviews. Gastroenterology & Hepatology·Luca FabrisMario Strazzabosco
Jan 24, 2019·Cold Spring Harbor Perspectives in Biology·Patrick G NeedhamJeffrey L Brodsky
Nov 13, 2019·Pediatric Pulmonology·Disha JoshiEric J Sorscher
Nov 7, 2019·International Journal of Molecular Sciences·Giulia AmicoDebora Baroni
Feb 16, 2019·American Journal of Respiratory Cell and Molecular Biology·Jenny P Nguyen, Jeremy A Hirota
Oct 19, 2019·Expert Review of Respiratory Medicine·Sarah L PatersonAlexander R Horsley
Jan 16, 2020·International Journal of Molecular Sciences·Samuel Estabrooks, Jeffrey L Brodsky
Oct 12, 2019·American Journal of Respiratory and Critical Care Medicine·Pierre-Régis BurgelUNKNOWN French Cystic Fibrosis Reference Network Study Group

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Methods Mentioned

BETA
ubiquitination
pharmacotherapy

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