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Cited by 161Cystic Fibrosis Research AdvancesInhalation and Respiratory Drug DeliveryGenetic and Kidney Cyst Diseases

Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators

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Pranke, Iwona M., Hatton, Aurélie, Simonin, Juliette, Jais, Jean Philippe, Le Pimpec-Barthes, Françoise, Carsin, Ania, Bonnette, Pierre, Fayon, Michael +10 more·2017·Scientific Reports
DOI 10.1038/s41598-017-07504-1PMC PMC5547155
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Abstract

Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆I scF/I+V ) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. I sc measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆I scF/I+V correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆I scF/I+V response to about 25% (SEM = 4.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEM = 4.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV 1 change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators.

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  1. [1]O’Sullivan BP Freedman SD Cystic fibrosis The Lancet 2009 373 1891 1904 10.1016/S0140-6736(09)60327-5 19403164 · DOI · Paper page
  2. [2]Pranke IM Sermet-Gaudelus I Biosynthesis of cystic fibrosis transmembrane conductance regulator Int. J. Biochem. Cell Biol. 2014 52 26 38 10.1016/j.biocel.2014.03.020 24685677 · DOI
  3. [3]Van Goor F Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770 Proc. Natl. Acad. Sci. USA 2009 106 18825 18830 10.1073/pnas.0904709106 19846789 PMC2773991 · DOI
  4. [4]Accurso FJ Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation N. Engl. J. Med. 2010 363 1991 2003 10.1056/NEJMoa0909825 21083385 PMC3148255 · DOI
  5. [5]Accurso FJ Sweat chloride as a biomarker of CFTR activity: proof of concept and ivacaftor clinical trial data J. Cyst. Fibros. 2014 13 139 147 10.1016/j.jcf.2013.09.007 24660233 PMC4102431 · DOI
  6. [6]Boeck KD Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation J. Cyst. Fibros. 2014 13 674 680 10.1016/j.jcf.2014.09.005 25266159 · DOI
  7. [8]Wainwright CE Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR N. Engl. J. Med. 2015 373 220 231 10.1056/NEJMoa1409547 25981758 PMC4764353 · DOI · Paper page
  8. [9]Veit G Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression Sci. Transl. Med. 2014 6 246ra97 10.1126/scitranslmed.3008889 25101887 PMC4467693 · DOI · Paper page
  9. [10]Cholon DM Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis Sci. Transl. Med. 2014 6 246ra96 10.1126/scitranslmed.3008680 25101886 PMC4272825 · DOI · Paper page
  10. [11]Meng X Two Small Molecules Restore Stability to a Subpopulation of the Cystic Fibrosis Transmembrane Conductance Regulator with the Predominant Disease-causing Mutation J. Biol. Chem. 2017 292 3706 3719 10.1074/jbc.M116.751537 28087700 PMC5339754 · DOI
  11. [12]Birket SE Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy Am. J. Physiol. Lung Cell. Mol. Physiol. 2016 310 L928 939 10.1152/ajplung.00395.2015 26968770 PMC4896103 · DOI
  12. [13]Phuan P-W Potentiators of Defective ΔF508-CFTR Gating that Do Not Interfere with Corrector Action Mol. Pharmacol. 2015 88 791 799 10.1124/mol.115.099689 26245207 PMC4576684 · DOI
  13. [14]Awatade NT Measurements of Functional Responses in Human Primary Lung Cells as a Basis for Personalized Therapy for Cystic Fibrosis EBioMedicine 2014 2 147 153 10.1016/j.ebiom.2014.12.005 26137539 PMC4484512 · DOI
  14. [15]Van Goor F 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 1130 10.1152/ajplung.00169.2005 16443646 · DOI
  15. [16]Neuberger T Burton B Clark H Van Goor F Use of primary cultures of human bronchial epithelial cells isolated from cystic fibrosis patients for the pre-clinical testing of CFTR modulators Methods Mol. Biol. Clifton NJ 2011 741 39 54 10.1007/978-1-61779-117-8_4 21594777 · DOI
  16. [17]de Courcey F Development of primary human nasal epithelial cell cultures for the study of cystic fibrosis pathophysiology Am. J. Physiol. Cell Physiol. 2012 303 C1173 1179 10.1152/ajpcell.00384.2011 23015550 · DOI
  17. [18]Mosler K Feasibility of nasal epithelial brushing for the study of airway epithelial functions in CF infants J. Cyst. Fibros. 2008 7 44 53 10.1016/j.jcf.2007.04.005 17553758 · DOI
  18. [19]McDougall CM Nasal epithelial cells as surrogates for bronchial epithelial cells in airway inflammation studies Am. J. Respir. Cell Mol. Biol. 2008 39 560 568 10.1165/rcmb.2007-0325OC 18483420 PMC2643208 · DOI
  19. [20]Lucarelli M A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation Genet. Med. 2010 12 548 555 10.1097/GIM.0b013e3181ead634 20706124 · DOI
  20. [21]Guinamard R Akabas MH Arg352 is a major determinant of charge selectivity in the cystic fibrosis transmembrane conductance regulator chloride channel Biochemistry (Mosc.) 1999 38 5528 5537 10.1021/bi990155n 10220340 · DOI
  21. [22]Ferec, C. & Cutting, G. R. Assessing the Disease-Liability of Mutations in CFTR. Cold Spring Harb. Perspect. Med. 2, (2012). PMC3543074 23209179
  22. [23]Highsmith WE Identification of a splice site mutation (2789 + 5 G > A) associated with small amounts of normal CFTR mRNA and mild cystic fibrosis Hum. Mutat. 1997 9 332 338 10.1002/(SICI)1098-1004(1997)9:4<332::AID-HUMU5>3.0.CO;2-7 9101293 · DOI
  23. [24]Green DM Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients Respir. Res. 2010 11 140 10.1186/1465-9921-11-140 20932301 PMC2964615 · DOI
  24. [25]Devalia JL Sapsford RJ Wells CW Richman P Davies RJ Culture and comparison of human bronchial and nasal epithelial cells in vitro Respir. Med. 1990 84 303 312 10.1016/S0954-6111(08)80058-3 2236758 · DOI
  25. [26]Pitkänen OM Smith D O’Brodovich H Otulakowski G Expression of alpha-, beta-, and gamma-hENaC mRNA in the human nasal, bronchial, and distal lung epithelium Am. J. Respir. Crit. Care Med. 2001 163 273 276 10.1164/ajrccm.163.1.9909114 11208656 · DOI
  26. [27]Gentzsch M Pharmacological Rescue of Conditionally Reprogrammed Cystic Fibrosis Bronchial Epithelial Cells Am. J. Respir. Cell Mol. Biol. 2016 PMC5449492 27983869
  27. [28]Reynolds SD Airway Progenitor Clone Formation Is Enhanced by Y-27632-Dependent Changes in the Transcriptome Am. J. Respir. Cell Mol. Biol. 2016 55 323 336 10.1165/rcmb.2015-0274MA 27144410 PMC5023026 · DOI
  28. [29]Tosoni K Cassidy D Kerr B Land SC Mehta A Using Drugs to Probe the Variability of Trans-Epithelial Airway Resistance PloS One 2016 11 e0149550 10.1371/journal.pone.0149550 26926476 PMC4771809 · DOI
  29. [30]Bangel N Dahlhoff C Sobczak K Weber W-M Kusche-Vihrog K Upregulated expression of ENaC in human CF nasal epithelium J. Cyst. Fibros. 2008 7 197 205 10.1016/j.jcf.2007.07.012 17766193 · DOI
  30. [31]Itani OA Human cystic fibrosis airway epithelia have reduced Cl− conductance but not increased Na + conductance Proc. Natl. Acad. Sci. USA 2011 108 10260 10265 10.1073/pnas.1106695108 21646513 PMC3121869 · DOI
  31. [32]Fischer H Illek B Finkbeiner WE Widdicombe JH Basolateral Cl channels in primary airway epithelial cultures Am. J. Physiol. Lung Cell. Mol. Physiol. 2007 292 L1432 1443 10.1152/ajplung.00032.2007 17322286 · DOI
  32. [33]Wiszniewski L Long-term cultures of polarized airway epithelial cells from patients with cystic fibrosis Am. J. Respir. Cell Mol. Biol. 2006 34 39 48 10.1165/rcmb.2005-0161OC 16179582 · DOI
  33. [34]Cutting GR Cystic fibrosis genetics: from molecular understanding to clinical application Nat. Rev. Genet. 2015 16 45 56 10.1038/nrg3849 25404111 PMC4364438 · DOI
  34. [35]Van Goor F Yu H Burton B Hoffman BJ Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function J. Cyst. Fibros. 2014 13 29 36 10.1016/j.jcf.2013.06.008 23891399 · DOI
  35. [36]Terlizzi V Clinical expression of patients with the D1152H CFTR mutation J. Cyst. Fibros. 2015 14 447 452 10.1016/j.jcf.2014.12.012 25583415 · DOI
  36. [37]Dekkers JF Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis Sci. Transl. Med. 2016 8 344ra84 344ra84 10.1126/scitranslmed.aad8278 27334259 · DOI · Paper page
  37. [38]Gruenert DC Finkbeiner WE Widdicombe JH Culture and transformation of human airway epithelial cells Am. J. Physiol. - Lung Cell. Mol. Physiol. 1995 268 L347 L360 7900815
  38. [40]Bitam S An unexpected effect of TNF-α on F508del-CFTR maturation and function F1000Research 2015 4 218 26594334 PMC4648213
  39. [41]McCloy RA Partial inhibition of Cdk1 in G 2 phase overrides the SAC and decouples mitotic events Cell Cycle Georget. Tex 2014 13 1400 1412 10.4161/cc.28401 PMC4050138 24626186 · DOI
  40. [42]Sermet-Gaudelus I Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport Am. J. Respir. Crit. Care Med. 2010 182 929 936 10.1164/rccm.201003-0382OC 20538955 · DOI

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Authors
Pranke, I. M., Hatton, A., Simonin, J., Jais, J. P., Le Pimpec-Barthes, F., Carsin, A., Bonnette, P., Fayon, M., Stremler-Le Bel, N., Grenet, D., Thumerel, M., Mazenq, J., Urbach, V., Mesbahi, M., Girodon-Boulandet, E., Hinzpeter, A., Edelman, A., & Sermet-Gaudelus, I.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Hôpital de la Timone (FR)
  • Hôpital Foch (FR)
  • Hôpital Pellegrin (FR)
  • Hôpital Cochin (FR)
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-08-07
Volume
7
Issue
1
Pages
7375-7375
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-07504-1
PMC
PMC5547155
OpenAlex
W2741556432
Cited by
161
References
2
Citations by year
2026: 9 · 2025: 15 · 2024: 14 · 2023: 14 · 2022: 21 · 2021: 32 · 2020: 20 · 2019: 18 · 2018: 15 · 2017: 3
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
American Breast Cancer Foundation
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
Keywords
cystic fibrosis, CFTR, CFTR modulators, CFTR correctors, lumacaftor, tezacaftor, F508del mutation, nasal epithelial cells, nasal potential difference, short-circuit current, predictive biomarkers, FEV1 response, patient response variability
MeSH terms
Aminopyridines, Cells, Cultured, Chlorides, Cystic Fibrosis, Epithelial Cells, Homozygote, Humans, Indoles, Mutation, Nasal Mucosa, Respiratory Function Tests, Biomarkers, Treatment Outcome, Cell Culture Techniques, Cystic Fibrosis Transmembrane Conductance Regulator, Benzodioxoles

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