Individualized medicine using intestinal responses to CFTR potentiators and correctors

Pediatric Pulmonology

Volumn 51, Issue , 2016, Pages S23-S34

  Beekman, Jeffrey M ^a  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

biomarkers of CFTR function; CFTR protein repairing drugs; intestinal organoids; rectal biopsies

Indexed keywords

CARBACHOL; CURCUMIN; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; FORSKOLIN; GENISTEIN; IVACAFTOR; LUMACAFTOR;

CONFOCAL MICROSCOPY; CYSTIC FIBROSIS; CYTOPLASM; DRUG EFFICACY; DRUG POTENTIATION; FORCED EXPIRATORY VOLUME; GENOTYPE ENVIRONMENT INTERACTION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INTESTINAL CURRENT MEASUREMENT; INTESTINE PARAMETERS; LIMIT OF QUANTITATION; PATHOGENESIS; PHASE 3 CLINICAL TRIAL (TOPIC); PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; RECTUM BIOPSY; REVIEW; TREATMENT RESPONSE;

EID: 84988530096     PISSN: 87556863     EISSN: 10990496     Source Type: Journal    
DOI: 10.1002/ppul.23553     Document Type: Review

References (75)

1. De Boeck K, Amaral MD. Rapid review progress in therapies for cystic fibrosis Lancet Respir Med 2016; 4:662–674.
2. Quon BS, Rowe SM. New and emerging targeted therapies for cystic fibrosis. BMJ 2016; 352:i859.
3. Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP, TRAFFIC study group, TRANSPORT study group. Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for phe508del CFTR. N Engl J Med 2015; 373:220–231.
4. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS. VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365:1663–1672.
5. Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet 2015; 16:45–56.
6. Vanscoy LL, Blackman SM, Collaco JM, Bowers A, Lai T, Naughton K, Algire M, McWilliams R, Beck S, Hoover-Fong J, Hamosh A, Cutler D, Cutting GR. Heritability of lung disease severity in cystic fibrosis. Am J Respir Crit Care Med 2007; 175:1036–1043.
7. Riordan JR. CFTR function and prospects for therapy. Annu Rev Biochem 2008; 77:701–726.
8. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993; 73:1251–1254.
9. Bell SC, De Boeck K, Amaral MD. New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Pharmacol Ther 2015; 145:19–34.
10. Veit G, Avramescu RG, Chiang AN, Houck SA, Cai Z, Peters KW, Hong JS, Pollard HB, Guggino WB, Balch WE, Skach WR, Cutting GR, Frizzell RA, Sheppard DN, Cyr DM, Sorscher EJ, Brodsky JL, Lukacs GL. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell 2016; 27:424–433.
11. Rowe SM, Verkman AS. Cystic fibrosis transmembrane regulator correctors and potentiators. Cold Spring Harb Perspect Med 2013; 3:pii: a009761.
12. Van Goor F, Hadida S, Grootenhuis PDJ, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA 2009; 106:18825–18830.
13. De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros 2014; 13:674–680.
14. Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 2010; 363:1991–2003.
15. Davies JC, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, Southern KW, Robertson S, Green Y, Cooke J, Rosenfeld M, KIWI Study Group. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a gating mutation (KIWI): an open-label, single arm study. Lancet Respir Med 2016; 4:1–9.
16. Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, Rubenstein RC, Higgins M. VX11-770-110 (KONDUCT) Study Group. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med 2015; 3:524–533.
17. Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature 1993; 362:160–164.
18. Van Goor F, Hadida S, Grootenhuis PDJ, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu PA. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA 2011; 108:18843–18848.
19. Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS, Ashlock MA, Ballmann M, Boyle MP, Bronsveld I, Campbell PW, De Boeck K, Donaldson SH, Dorkin HL, Dunitz JM, Durie PR, Jain M, Leonard A, McCoy KS, Moss RB, Pilewski JM, Rosenbluth DB, Rubenstein RC, Schechter MS, Botfield M, Ordoñez CL, Spencer-Green GT, Vernillet L, Wisseh S, Yen K, et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 2012; 67:12–18.
20. Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, Huang X, Waltz D, Patel NR, Rodman D, on behalf of the VX09-809-102 study group. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase randomised controlled trial. Lancet Respir Med 2014; 2:527–538.
21. Harrison MJ, Ronan NJ, Khan KA, O'Callaghan G, Murphy DM, Plant BJ. Pulmonary pharmacology & therapeutics. ‎Pulm Pharmacol Ther 2015; 31:49–50.
22. Trittler R, Hug MJ. PKP-017 Monitoring of ivacaftor serum levels. Eur J Hosp Pharm 2014; 21:A143–A144.
23. VanDevanter DR, Kahle JS, O'Sullivan AK, Sikirica S, Hodgkins PS. Cystic fibrosis in young children: a review of disease manifestation, progression, and response to early treatment. J Cyst Fibros 2016; 15:147–157.
24. Munck A, Languepin J, Debray D, Lamireau T, Abely M, Huet F, Maudinas R, Michaud L, Mas E. Management of pancreatic, gastrointestinal and liver complications in adult cystic fibrosis. Rev Mal Respir 2015; 32:566–585.
25. Bodewes FAJA, Verkade HJ, Taminiau JAJM, Borowitz D, Wilschanski M. Working group C​ystic Fibrosis and Pancreatic Disease of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). Cystic fibrosis and the role of gastrointestinal outcome measures in the new era of therapeutic CFTR modulation. J Cyst Fibros 2015; 14:169–177.
26. Beekman JM, Sermet-Gaudelus I, De Boeck K, Gonska T, Derichs N, Mall MA, Mehta A, Martin U, Drumm M, Amaral MD. CFTR functional measurements in human models for diagnosis, prognosis and personalized therapy. J Cyst Fibros 2014; 13:363–372.
27. Servidoni MF, Sousa M, Vinagre AM, Cardoso SR, Ribeiro MA, Meirelles LR, de Carvalho RB, Kunzelmann K, Ribeiro AF, Ribeiro JD, Amaral MD. Rectal forceps biopsy procedure in cystic fibrosis: technical aspects and patients perspective for clinical trials feasibility. BMC Gastroenterol 2013; 13:91.
28. Veeze HJ, Sinaasappel M, Bijman J, Bouquet J, de Jonge HR. Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis. Gastroenterology 1991; 101:398–403.
29. Veeze HJ, Halley DJ, Bijman J, de Jongste JC, de Jonge HR, Sinaasappel M. Determinants of mild clinical symptoms in cystic fibrosis patients. Residual chloride secretion measured in rectal biopsies in relation to the genotype. J Clin Invest 1994; 93:461–466.
30. De Jonge HR, Ballmann M, Veeze H, Bronsveld I, Stanke F, Tümmler B, Sinaasappel M. Ex vivo CF diagnosis by intestinal current measurements (ICM) in small aperture, circulating Ussing chambers. J Cyst Fibros 2004; 3:159–163.
31. Bronsveld I, Mekus F, Bijman J, Ballmann M, Greipel J, Hundrieser J, Halley DJ, Laabs U, Busche R, de Jonge HR, Tümmler B, Veeze HJ. Residual chloride secretion in intestinal tissue of deltaF508 homozygous twins and siblings with cystic fibrosis. The European CF Twin and Sibling Study Consortium. Gastroenterology 2000; 119:32–40.
32. Bronsveld I, Mekus F, Bijman J, Ballmann M, de Jonge HR, Laabs U, Halley DJ, Ellemunter H, Mastella G, Thomas S, Veeze HJ, Tümmler B. Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings. J Clin Invest 2001; 108:1705–1715.
33. de Nooijer RA, Nobel JM, Arets HGM, Bot AG, van Berkhout FT, de Rijke YB, de Jonge HR, Bronsveld I. Assessment of CFTR function in homozygous R117H-7T subjects. J Cyst Fibros 2011; 10:326–332.
34. Mall M, Kreda SM, Mengos A, Jensen TJ, Hirtz S, Seydewitz HH, Yankaskas J, Kunzelmann K, Riordan JR, Boucher RC. The DeltaF508 mutation results in loss of CFTR function and mature protein in native human colon. Gastroenterology 2004; 126:32–41.
35. Hirtz S, Gonska T, Seydewitz HH, Thomas J, Greiner P, Kuehr J, Brandis M, Eichler I, Rocha H, Lopes A-I, Barreto C, Ramalho A, Amaral MD, Kunzelmann K, Mall M. CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. Gastroenterology 2004; 127:1085–1095.
36. Mall M, Hirtz S, Gonska T, Kunzelmann K. Assessment of CFTR function in rectal biopsies for the diagnosis of cystic fibrosis. J Cyst Fibros 2004; 3:165–169.
37. Mall M, Bleich M, Schürlein M, Kühr J, Seydewitz HH, Brandis M, Greger R, Kunzelmann K. Cholinergic ion secretion in human colon requires coactivation by cAMP. Am J Physiol 1998; 275:G1274–G1281.
38. Mall M, Wissner A, Seydewitz HH, Kuehr J, Brandis M, Greger R, Kunzelmann K. Defective cholinergic Cl(−) secretion and detection of K(+) secretion in rectal biopsies from cystic fibrosis patients. Am J Physiol Gastrointest Liver Physiol 2000; 278:G617–G624.
39. Sousa M, Servidoni MF, Vinagre AM, Ramalho AS, Bonadia LC, Felício V, Ribeiro MA, Uliyakina I, Marson FA, Kmit A, Cardoso SR, Ribeiro JD, Bertuzzo CS, Sousa L, Kunzelmann K, Ribeiro AF, Amaral MD. Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis. PLoS ONE 2012; 7:e47708.
40. Derichs N, Sanz J, Kanel Von T, Stolpe C, Zapf A, Tümmler B, Gallati S, Ballmann M. Intestinal current measurement for diagnostic classification of patients with questionable cystic fibrosis: validation and reference data. Thorax 2010; 65:594–599.
41. Clancy JP, Szczesniak RD, Ashlock MA, Ernst SE, Fan L, Hornick DB, Karp PH, Khan U, Lymp J, Ostmann AJ, Rezayat A, Starner TD, Sugandha SP, Sun H, Quinney N, Donaldson SH, Rowe SM, Gabriel SE. Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function. PLoS ONE 2013; 8:e73905.
42. Cohen-Cymberknoh M, Yaakov Y, Shoseyov D, Shteyer E, Schachar E, Rivlin J, Bentur L, Picard E, Aviram M, Israeli E, Kerem E, Wilschanski M. Evaluation of the intestinal current measurement method as a diagnostic test for cystic fibrosis. Pediatr Pulmonol 2013; 48:229–235.
43. Derichs N, Pinders-Kessler L, Bronsveld I, Scheinert S, Rückes-Nilges C, de Jonge HR, Naehrlich L. Multicenter European standardization and reference values for intestinal current measurement in rectal biopsies. Pediatr Pulmonol Suppl 2013; S36:300
44. Roth EK, Hirtz S, Duerr J, Wenning D, Eichler I, Seydewitz HH, Amaral MD, Mall MA. The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients. PLoS ONE 2011; 6:e24445.
45. Dekkers JF, Van Mourik P, Vonk AM, Kruisselbrink E, Berkers G, de Winter-de Groot KM, Janssens HM, Bronsveld I, der Ent van CK, De Jonge HR, Beekman JM. Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations. J Cyst Fibros 2016; DOI: 10.1016/j.jcf.2016.04.007
46. De Boeck K, Derichs N, Fajac I, de Jonge HR, Bronsveld I, Sermet I, Vermeulen F, Sheppard DN, Cuppens H, Hug M, Melotti P, Middleton PG, Wilschanski M, ECFS Diagnostic Network Working Group, EuroCareCF WP3 Group on CF diagnosis. New clinical diagnostic procedures for cystic fibrosis in Europe. J Cyst Fibros 2011; 10:S53–S66.
47. Thiagarajah JR, Verkman AS. Chloride channel-targeted therapy for secretory diarrheas. Curr Opin Pharmacol 2013; 13:888–894.
48. Graeber SY, Hug MJ, Sommerburg O, Hirtz S, Hentschel J, Heinzmann A, Dopfer C, Schulz A, Mainz JG, Tümmler B, Mall MA. Intestinal current measurements detect activation of mutant CFTR in patients with cystic fibrosis with the G551D mutation treated with ivacaftor. Am J Respir Crit Care Med 2015; 192:1252–1255.
49. van Koningsbruggen-Rietschel S, Naehrlich L. Cystic fibrosis transmembrane conductance regulator biomarkers in “real life”: can we evaluate individual efficacy of cystic fibrosis transmembrane conductance regulator therapy? Ther Adv Respir Dis 2015; 9:198–200.
50. Sato T, Clevers H. Growing self-Organizing mini-Guts from a single intestinal stem cell: mechanism and applications. Science 2013; 340:1190–1194.
51. Sato T, Stange DE, Ferrante M, Vries RGJ, van Es JH, van den Brink S, Van Houdt WJ, Pronk A, van Gorp J, Siersema PD, Clevers H. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 2011; 141:1762–1772.
52. Jung P, Sato T, Merlos-Suárez A, Barriga FM, Iglesias M, Rossell D, Gallardo MM, Blasco MA, Sancho E, Clevers H, Batlle E. Isolation and in vitro expansion of human colonic stem cells. Nat Med 2011; 4:1225–1227.
53. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 2009; 459:262–265.
54. Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F, Verstegen MMA, Ellis E, van Wenum M, Fuchs SA, de Ligt J, van de Wetering M, Sasaki N, Boers SJ, Kemperman H, de Jonge J, Ijzermans JNM, Nieuwenhuis EES, Hoekstra R, Strom S, Vries RRG, van der Laan LJW, Cuppen E, Clevers H. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 2015; 160:299–312.
55. Middendorp S, Schneeberger K, Wiegerinck CL, Mokry M, Akkerman RDL, van Wijngaarden S, Clevers H, Nieuwenhuis EES. Adult stem cells in the small intestine are intrinsically programmed with their location-specific function. Stem Cells 2014; 32:1083–1091.
56. van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A, van Houdt W, van Gorp J, Taylor-Weiner A, Kester L, McLaren-Douglas A, Blokker J, Jaksani S, Bartfeld S, Volckman R, van Sluis P, Li VSW, Seepo S, Sekhar Pedamallu C, Cibulskis K, Carter SL, McKenna A, Lawrence MS, Lichtenstein L, Stewart C, Koster J, Versteeg R, van Oudenaarden A, Saez-Rodriguez J, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 2015; 161:933–945.
57. Dekkers JF, Wiegerinck CL, De Jonge HR, Bronsveld I, Janssens HM, de Winter-de Groot KM, Brandsma AM, de Jong NWM, Bijvelds MJC, Scholte BJ, Nieuwenhuis EES, van den Brink S, Clevers H, der Ent van CK, Middendorp S, Beekman JM. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med 2013; 19:939–945.
58. Dekkers JF, der Ent van CK, Beekman JM. Novel opportunities for CFTR-targeting drug development using organoids. Rare Dis 2014; 1:e27112.
59. Dekkers JF, Berkers G, Kruisselbrink E, Vonk A, De Jonge HR, Janssens HM, Bronsveld I, van de Graaf EA, Nieuwenhuis EES, Houwen RHJ, Vleggaar FP, Escher JC, de Rijke YB, Majoor CJ, Heijerman HGM, de Winter-de Groot KM, Clevers H, der Ent van CK, Beekman JM. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci Transl Med 2016; 8:344ra84.
60. Foulke-Abel J, In J, Yin J, Zachos NC, Kovbasnjuk O, Estes MK, De Jonge H, Donowitz M. Human Enteroids as a Model of Upper Small Intestinal Ion Transport Physiology and Pathophysiology. Gastroenterology 2016; 150:638–649.
61. Van Goor F, Straley KS, Cao D, González J, Hadida S, Hazlewood A, Joubran J, Knapp T, Makings LR, Miller M, Neuberger T, Olson E, Panchenko V, Rader J, Singh A, Stack JH, Tung R, Grootenhuis PDJ, Negulescu P. Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol Lung Cell Mol Physiol 2006; 290:L1117–L1130.
62. Moon C, VanDussen KL, Miyoshi H, Stappenbeck TS. Development of a primary mouse intestinal epithelial cell monolayer culture system to evaluate factors that modulate IgA transcytosis. Mucosal Immunol 2014; 7:818–828.
63. Ommen DDZ-V, Vijftigschild LAW, Kruisselbrink E, Vonk AM, Dekkers JF, Janssens HM, de Winter-de Groot KM, van der Ent CK, Beekman JM. Limited premature termination codon suppression by read-through agents incystic. J Cyst Fibros 2016; 15:158–162.
64. Dekkers R, Vijftigschild LAW, Vonk AM, Kruisselbrink E, de Winter-de Groot KM, Janssens HM, van der Ent CK, Beekman JM. A bioassay using intestinal organoids to measure CFTR modulators in human plasma. J Cyst Fibros 2015; 14:178–181.
65. Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, Roldan A, Verkman AS, Kurth M, Simon A, Hegedus T, Beekman JM, Lukacs GL. Mechanism-based corrector combination restores ΔF508-CFTR folding and function. Nat Chem Biol 2013; 9:444–454.
66. Dekkers JF, Gogorza Gondra RA, Kruisselbrink E, Vonk AM, Janssens HM, de Winter-de Groot KM, der Ent van CK, Beekman JM. Optimal correction of distinct CFTR folding mutants in rectal cystic fibrosis organoids. Eur Resp J 2016; 48:451–458.
67. Vidović D, Carlon MS, da Cunha MF, Dekkers JF, Hollenhorst MI, Bijvelds MJC, Ramalho AS, Van den Haute C, Ferrante M, Baekelandt V, Janssens HM, De Boeck K, Sermet-Gaudelus I, De Jonge HR, Gijsbers R, Beekman JM, Edelman A, Debyser Z. RAAV-CFTRćR rescues the cystic fibrosis phenotype in human intestinal organoids and cystic fibrosis mice. Am J Respir Crit Care Med 2016; 193:288–298.
68. Schwank G, Koo B-K, Sasselli V, Dekkers JF, Heo I, Demircan T, Sasaki N, Boymans S, Cuppen E, der Ent van CK, Nieuwenhuis EES, Beekman JM, Clevers H. Brief Report. Cell Stem Cell 2013; 13:653–658.
69. Rowe SM, Liu B, Hill A, Hathorne H, Cohen M, Beamer JR, Accurso FJ, Dong Q, Ordoñez CL, Stone AJ, Olson ER, Clancy JP. VX06-770-101 Study Group. Optimizing nasal potential difference analysis for CFTR modulator development: assessment of ivacaftor in CF subjects with the G551D-CFTR mutation. PLoS ONE 2013; 8:e66955.
70. Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, Sagel SD, Khan U, Mayer-Hamblett N, Van Dalfsen JM, Joseloff E, Ramsey BW. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190:175–184.
71. Durmowicz AG, Witzmann KA, Rosebraugh CJ, Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest 2013; 143:14–18.
72. Knowles M, Gatzy J, Boucher R. Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. N Engl J Med 1981; 305:1489–1495.
73. De Boeck K, Kent L, Davies J, Derichs N, Amaral M, Rowe S, Middleton P, de Jonge H, Bronsveld I, Wilschanski M, Melotti P, Danner-Boucher I, Boerner S, Fajac I, Southern K, de Nooijer R, Bot A, de Rijke Y, de Wachter E, Leal T, Vermeulen F, Hug JM, Rault G, Nguyen-Khoa T, Barreto C, Proesmans M, Sermet-Gaudelus I, On behalf of the European Cystic Fibrosis Society Clinical Trial Network Standardisation Committee. Cftr biomarkers: time for promotion to surrogate endpoint? Eur Resp J 2013; 41:203–216.
74. Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet 2013; 45:1160–1167.
75. Collaco JM, Blackman SM, Raraigh KS, Corvol H, Rommens JM, Pace RG, Boëlle P-Y, McGready J, Sosnay PR, Strug LJ, Knowles MR, Cutting GR. Sources of variation in sweat chloride measurements in cystic fibrosis. Am J Respir Crit Care Med 2016; DOI: 10.1164/rccm.201603-0459oc