4,395
Views
24
CrossRef citations to date
0
Altmetric
Review

Discovery of CFTR modulators for the treatment of cystic fibrosis

ORCID Icon, &
Pages 897-913 | Received 30 Nov 2020, Accepted 31 Mar 2021, Published online: 13 Apr 2021

References

  • Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet. 2015 Jan;16(1):45–56.
  • Guggino WB, Stanton BA. New insights into cystic fibrosis: molecular switches that regulate CFTR. Nat Rev Mol Cell Biol. 2006 Jun;7(6):426–436.
  • Lopes-Pacheco M. CFTR modulators: the changing face of cystic fibrosis in the era of precision medicine. Front Pharmacol. 2020 Feb;21(10):1662.
  • Castellani C, Duff AA, Bell SC, et al. ECFS best practice guidelines: the version 2018 revision. J Cyst Fibros. 2018 Mar;17(2):153–178.
  • Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med. 2020 Jan;8(1):65–124.
  • Liu F, Zhang Z, Csanády L, et al. Molecular structure of the human CFTR ion channel. Cell. 2017 Mar 23;169(1):85–95. e8.
  • Zhang Z, Liu F, Chen J. Molecular structure of the ATP-bound-phosphorylated human CFTR. Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):12757–12762.
  • Kim SJ, Skach WR. Mechanisms of CFTR folding at the endoplasmic reticulum. Front Pharmacol. 2012 Dec;13(3):201.
  • Veit G, Avramescu RG, Chiang AN, et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell. 2016 Feb 1;27(3):424–433.
  • Lopes-Pacheco M. CFTR modulators: Shedding light on precision medicine for cystic fibrosis. Front Pharmacol. 2016 Sep;7:275.
  • Cheng SH, Gregory RJ, Marshall J, et al. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell. 1990 Nov 16;63(4):827–834.
  • Dalemans W, Barbry P, Champigny G, et al. Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature. 1991 Dec 19-26;354(6354):526–528.
  • Okiyoneda T, Barriève H, Bagdány M, et al. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science. 2010 Aug 13;329(5993):805–810.
  • Dukovski D, Villella A, Bastos C, et al. Amplifiers co-translationally enhance CFTR biosynthesis bia PCBP1-mediated regulation of CFTR mRNA. J Cystic Fibros. 2020 Sep;19(5):733–741.
  • Bardin P, Sonneville F, Corvol G, et al. Emerging microRNA therapeutic approaches for cystic fibrosis. Front Pharmacol. 2018;9:1113.
  • Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Eng J Med. 2011 Nov 3;365(18):1663–1672.
  • Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for phe508del CFTR. N Eng J Med. 2015 Jul 16;373(3):220–231.
  • Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor–Ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Eng J Med. 2017 Nov 23;377(21):2013–2023.
  • Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-Ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017 Nov 23;377(21):2024–2035.
  • Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019 Nov 23;394(10212):1940–1948.
  • Middleton PG, Mall MA, Drevínek P, et al. Elexacaftor-Texacaftor-Ivacaftor for cystic fibrosis with a single phe508del allele. N Eng J Med. 2019 Nov 7;381(19):1809–1819.
  • McKone EF, Borowitz D, Drevinek P, et al. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med. 2014 Nov;2(11):902–910.
  • Konstan MW, McKone EF, Moss RB, et al. assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017 Feb;5(2):107–118.
  • Avramescu RG, Kai Y, Xu H, et al. Mutation-specific downregulation of CFTR2 variants by gating potentiators. Hum Mol Genet. 2017 Desember 15;26(24):4873–4885.
  • Veit G, Da Fonte DF, Avramescu RG, et al. Mutation-specific dual potentiators maximize rescue of CFTR gating mutants. J Cyst Fibros. 2020 Mar;19(2):236–244.
  • Veit G, Roldan A, Hancock MA, et al. Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination. JCI Insight. 2020 Sep 17;5(18):e139983.
  • Yu H, Burton B, Huang C-J, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cystic Fibros. 2012 May;11(3):237–245.
  • Van Goor F, Yu H, Burton B, et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29–36.
  • Han ST, Rab A, Pellicore MJ, et al. Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators. JCI Insight. 2018 Jul;3(14):e121159.
  • Lopes-Pacheco M, Boinot C, Sabirzhanova I, et al. Combination of correctors rescues CFTR transmembrane-domain mutants by mitigating their interactions with proteostasis. Cell Physiol Biochem. 2017;41(6):2194–2210.
  • Lopes-Pacheco M, Sabirzhanova I, Rapino D, et al. Correctors rescue CFTR mutations in nucleotide-binding domains 1 (NBD1) by modulating proteostasis. Chembiochem. 2016 Mar;17(6):493–505.
  • Rapino D, Sabirzhanova I, Lopes-Pacheco M, et al. Rescue of NBD2 mutants N1303K and S1235R of CFTR by small-molecule correctors and transcomplementation. PLoS One. 2015 Mar;10(3):e0119796.
  • Mou H, Vinarsky V, Tata PR, et al. Dual SMAD signaling inhibition enables long-term expansion of diverse epithelial basal cells. Cell Stem Cell. 2016 Aug 4;19(2):217–231.
  • Gianotti A, Delpiano L, Caci E. In vitro methods for the development and analysis of Human Primary Airway Epithelia. Front Pharmacol. 2018 Oct;26(9):1176.
  • Dekkers JF, Wiegerinck CL, De Jonge HR, et al. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med. 2013 Jul;19(7):939–945.
  • Dekkers JF, Berkers G, Kruisselbrink E, et al. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci Transl Med. 2016 Jun 22;8(344):344ra84.
  • Sachs N, Papaspyropoulos A, Zomer-van Ommen DD, et al. Long-term expanding human airway organoids for disease modeling. Embo J. 2019 Feb 15;38(4):e100300.
  • Verkman AS, Lukacs GL, Galietta LJV. CFTR chloride channel drug discovery—inhibitors as antidiarrheals and activators for therapy of cystic fibrosis. Curr Pharm Des. 2006;12(18):2235–2247.
  • Verkman AS, Galietta LJV. Chloride channels as drug targets. Nat Rev Drug Discov. 2009 Feb;8(2):153–171.
  • Van Goor D, Hadida S, Grootenhuis PDJ, et al. Rescue of CF airway epithelial function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18825–18830.
  • Pedemonte N, Lukacs GL, Du K, et al. Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. J Clin Invest. 2005 Sep;115(9):2564–2571.
  • Sheppard DN, Carson MR, Ostedgaard LS, et al. Expression of cystic fibrosis transmembrane conductance regulator in a model epithelium. Am J Physiol. 1994 Apr;266(4 Pt 1):L405–L413.
  • Galietta LJ, Springsteel MF, Eda M, et al. Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds. J Biol Chem. 2001 Jun 8;276(23):19723–19728.
  • Caputo A, Hinzpeter A, Caci E, et al. Mutation-specific potency and efficacy of cystic fibrosis transmembrane conductance regulator chloride channel potentiators. J Pharmacol Exp Ther. 2009 Sep;330(3):783–791.
  • Van Goor F, Straley KS, Cao D, et al. 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 Jun;290(6):L1117–L1130.
  • Van Goor F, Hadida S, Grootenhuis PDJ, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigation drug VX-809. Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18843–18848.
  • Robert R, Carlile GW, Pavel C, et al. Structural analog of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect. Mol Pharmacol. 2008 Feb;73(2):478–489.
  • Carlile GW, Robert R, Zhang D, et al. Correctors of protein trafficking defects identified by a novel high-throughput screening assay. Chembiochem. 2007 Jun 18;8(9):1012–1020.
  • Sampson HM, Robert R, Liao J, et al. Identification of a NBD1-binding pharmacological chaperone that corrects the trafficking defect of F508del-CFTR. Chem Biol. 2011 Feb 25;18(2):231–242.
  • Prins S, Langron E, Hastings C, et al. Fluorescence assay for simultaneous quantification of CFTR ion-channel function and plasma membrane proximity. J Biol Chem. 2020 Sep;295(49):16529–16544.
  • Pedemonte N, Tomati V, Sondo E, et al. Influence of cell background on pharmacological rescue of mutant CFTR. Am J Physiol Cell Physiol. 2010 Apr;298(4):C866–C874.
  • Ahmadi S, Bozoky Z, Di Paola M, et al. Phenotypic profiling of CFTR modulators in patient-derived respiratory epithelia. NPJ Genom Med. 2017 Apr;2(1):12.
  • Cozens AL, Yezzi MJ, Kunzelmann K, et al. CFTR expression and chloride secretion in polarized immortal human bronchial epithelial cells. Am J Respir Cell Mol Biol. 1994 Jan;10(1):38–47.
  • Gottschalk LB, Vecchio-Pagan B, Sharma N, et al. Creation and characterization of an airway epithelial cell line for stable expression of CFTR variants. J Cyst Fibros. 2006 May;15(3):285–294.
  • Veit G, Xu H, Dreano E, et al. Structure-guided combination to potentially improve the function of mutant CFTRs. Nat Med. 2018 Nov;24(11):1732–1742.
  • Donaldson SH, Pilewski JM, Griese M, et al. Tezacaftor/Ivacaftor in subjects with cystic fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. Am J Respir Crit Care Med. 2018 Jan 15;197(2):214–224.
  • Ai T, Bompadre SG, Wang X, et al. Copsaicin potentiates wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride-channel currents. Mol Pharmacol. 2004 Jun;65(6):1415–1426.
  • Moran O, Zegarra-Moran O. A quantitative description of the activation and inhibition of CFTR by potentiators: Genistein. FEBS Lett. 2005 Jul 18;579(18):3979–3983.
  • Cai Z, Taddei A, Sheppard DN. Differential sensitivity of the cystic fibrosis (CF)-associated mutants G551D and G1349D to potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl– channel. J Biol Chem. 2006 Jan 27;281(4):1970–1977.
  • Liu F, Zhang Z, Levit A, et al. Structural identification of a hotspot on CFTR for potentiation. Science. 2019 Jun 21;364(6446):1184–1188.
  • Yeh H-I, Qui L, Sohma Y, et al. Identifying the molecular target site for CFTR potentiators GLPG1837 and VX-770. J Gen Physiol. 2019 Jul 1;151(7):912–928.
  • Li H, Pesce E, Sheppard DN, et al. Therapeutic approaches to CFTR dysfunction: From discovery to drug development. J Cyst Fibros. 2018 Mar;17(2S(2):S14–S21.
  • Balch WE, Morimoto RI, Dillin A, et al. Adapting proteostasis for disease intervention. Science. 2008 Feb 15;319(5865):916–919.
  • Sondo E, Pesce E, Tomati V, et al. RNF5, DAB2 and friends: novel drug targets for cystic fibrosis. Curr Pharm Des. 2017;23(1):176–186.
  • Okiyoneda T, Veit G, Dekkers JF, et al. Mechanism-based corrector combination restores ΔF508del-CFTR folding and function. Nat Chem Biol. 2013 Jul;9(7):444–454.
  • Mendoza JL, Schmidt A, Li Q, et al. Requirements for efficient correction of ΔF508del CFTR revealed by analyses of evolved sequences. Cell. 2012 Jan 20;148(1–2):164–174.
  • Rabeh WM, Bossard F, Xu H, et al. Correction of both NBD1 energetics and domain interface is required to restore ΔF508 CFTR folding and function. Cell. 2012 Jan 20;148(1–2):150–163.
  • Lopes-Pacheco M, Silva IAL, Turner MJ, et al. Characterization of the mechanism of action of RDR01752, a novel corrector of F508del-CFTR. Biochem Pharmacol. 2020 Oct;180:114133.
  • Laselva O, Bartlett C, Gunawardena TNA, et al. Rescue of multiple class II CFTR mutations by elexacaftor+tezacaftor+ivacaftor mediated in part by the dual activities of elexacaftor as both corrector and potentiator. Eur Respir J. 2020;2002774. 10.1183/13993003.02774-2020.
  • Veit G, Vaccarin C, Lukacs GL. Elexacaftor co-potentiates the activity of F508del and gating mutants of CFTR.. J Cyst Fibros. 2021. DOI:10.1016/j.jcf.2021.03.011.
  • Tomati V, Caci E, Ferrera L, et al. Thymosin alpha-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia. JCI Insight. 2018 Feb 8;3(3):e98699.
  • Armirotti A, Tomati V, Matthes E, et al. Bioactive thymosin Alpha-1 Does Not Influence F508del-CFTR Maturation and Activity. Sci Rep. 2019 Jul 16;9(1):10310.
  • Skilton M, Krishan A, Patel S, et al. Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis. Cochrane Database Syst Rev. 2019 Jan;7(1):CD009841.
  • Durmowicz AG, Lim R, Rogers H, et al. The U.S. food and drug administration’s experience with ivacaftor in cystic fibrosis. establishing efficacy using in vitro date in Lieu of a Clinical Trial. Ann Am Thorac Soc. 2018 Jan;15(1):1–2.
  • Vertex Pharmaceuticals Inc. Highlights of prescribing information: kalydeco® (ivacaftor) – Revised: desember/2020. Available online at: https://pi.vrtx.com/files/uspi_ivacaftor.pdf (accessed 2021 Mar 16).
  • De Boeck K, Munck A, Walkers S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014 Dec;13(6):674–680.
  • Guimbellot J, Solomon GM, Baines A, et al. Effectiveness of ivacaftor in cystic fibrosis patients with non-G551D gating mutations. J Cyst Fibros. 2019 Jan;18(1):102–109.
  • Rowe SM, Pyle LC, Jurkevante A, et al. DeltaF508 CFTR processing correction and activity in polarized airway and non-airway cell monolayers. Pulm Pharmacol Ther. 2010 Aug;23(4):268–278.
  • Vertex Pharmaceuticals Inc. Highlights of prescribing information: symdeko® (tezacaftor/ivacaftor) – Revised: desember/2020. Available online at: https://pi.vrtx.com/files/uspi_tezacaftor_ivacaftor.pdf (accessed 2021 Mar 16).
  • Vertex Pharmaceuticals Inc. Highlights of prescribing information: trikafta® (elexacaftor/tezacaftor/ivacaftor) – Revised: desember/2020. Available online at: https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf (accessed 2021 Mar 16).
  • Sosnay PR, Siklosi KR, Van Goor F, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45(10):1160–1167.
  • Du K, Lukacs GL. Cooperative assembly and misfolding of CFTR domains in vivo. Mol Biol Cell. 2009 Apr;20(7):1903–1915.
  • Lin WY, Sohma Y, Hwang TC. synergistic potentiation of cystic fibrosis transmembrane conductance regulator gating by two chemically distinct potentiators, Ivacaftor (VX-770) and 5-Nitro-2-(3-Phenylpropylamino) Benzoate. Mol Pharmacol. 2016 Sep;90(3):275–285.
  • Phuan PW, Son JH, Tan JA, et al. Combination potentiator (‘co-potentiator’) therapy for CF caused by CFTR mutants, including N1303K, that are poorly responsive to single potentiators. J Cyst Fibros. 2018 Sep;17(5):595–606.
  • Cho DY, Zhang S, Lazrak A, et al. Resveratrol and ivacaftor are additive G551D CFTR-channel potentiators: therapeutic implications for cystic fibrosis sinus disease. Int Forum Allergy Rhinol. 2019 Jan;9(1):100–105.
  • Dekkers JF, Van Mourik P, Vonk AM, et al. Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations. J Cyst Fibros. 2016 Sep;15(5):568–578.
  • Phuan PW, Tan JA, Rivera AA, et al. Nanomolar-potency ‘co-potentiator’ therapy for cystic fibrosis caused by a defined subset of minimal function CFTR mutants. Sci Rep. 2019 Nov 27;9(1):17640.
  • Lewis HA, Buchanan SG, Burley SK, et al. Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. Embo J. 2004 Jan 28;23(2):282–293.
  • Lewis HA, Zhao X, Wang C, et al. Impact of the deltaF508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure. J Biol Chem. 2005 Jan 14;280(2):1346–1353.
  • Huang SY, Bolser D, Liu HY, et al. Molecular modeling of the heterodimer of human CFTR’s nucleotide-binding domains using a protein-protein docking approach. J Mol Graph Model. 2009 Apr;27(7):822–828.
  • Moran O, Galietta LJ, Zegarra-Moran O. Binding site of activators of the cystic fibrosis transmembrane conductance regulator in the nucleotide binding domains. Cell Mol Life Sci. 2005 Feb;62(4):446–460.
  • Serohijos AW, Hegedus T, Aleksandrov AA, et al. Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3256–3261.
  • Dalton J, Kalid O, Schushan M, et al. New model of cystic fibrosis transmembrane conductance regulator proposes active channel-like conformation. J Chem Inf Model. 2012 Jul 23;52(7):1842–1853.
  • Corradi V, Vergani P, Tieleman DP. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR): CLOSED AND OPEN STATE CHANNEL MODELS. J Biol Chem. 2015 Sep 18;290(38):22891–22906.
  • Mornon JP, Lehn P, Callebaut I. Molecular models of the open and closed states of the whole human CFTR protein. Cell Mol Life Sci. 2009 Nov;66(21):3469–3486.
  • He L, Kota P, Aleksandrov AA, et al. Correctors of DeltaF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein. Faseb J. 2013 Feb;27(2):536–545.
  • Farinha CM, King-Underwood J, Sousa M, et al. Revertants, low temperature, and correctors reveal the mechanism of F508del-CFTR rescue by VX-809 and suggest multiple agents for full correction. Chem Biol. 2013 Jul 25;20(7): 943–955.
  • Kalid O, Mense M, Fischman S, et al. Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening. J Comput Aided Mol Des. 2010 Dec;24(12):971–991.
  • Odolczyk N, Fritsch J, Norez C, et al. Discovery of novel potent DeltaF508-CFTR correctors that target the nucleotide binding domain. EMBO Mol Med. 2013 Oct;5(10):1484–1501.
  • Parodi A, Righetti G, Pesce E, et al. Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays. Eur J Med Chem. 2020 Sep 12;208:112833.
  • Liessi N, Cichero E, Pesce E, et al. Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools. Eur J Med Chem. 2018 Jan 20;144:179–200.
  • Molinski SV, Shahani VM, Subramanian AS, et al. Comprehensive mapping of cystic fibrosis mutations to CFTR protein identifies mutation clusters and molecular docking predicts corrector binding site. Proteins. 2018 Aug;86(8):833–843.
  • Ren HY, Grove DE, De La Rosa O, et al. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell. 2013 Oct;24(19):3016–3024.
  • Berg A, Halowell S, Tibbetts M, et al. High-throughput surface liquid absorption and secretion assays to identify F508del CFTR correctors using patient primary airway epithelial cultures. SLAS Discov. 2019;24(7):724–737.
  • Liu X, Krawczyk E, Suprynowicz FA, et al. Conditional reprogramming and long-term expansion of normal and tumor cells from human biospecimens. Nat Protoc. 2017 Feb;12(2):439–451.
  • Liu X, Ory V, Chapman S, et al. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am J Pathol. 2012 Feb;180(2):599–607.
  • Wu X, Wang S, Li M, et al. Conditional reprogramming: next generation cell culture. Acta Pharm Sin B. 2020 Aug;10(8):1360–1381.
  • Muller L, Brighton LE, Carson JL, et al. Culturing of human nasal epithelial cells at the air liquid interface. J Vis Exp. 2013 Oct;08(80):e50646.
  • Valley HC, Bukis KM, Bell A, et al. Isogenic cell models of cystic fibrosis-causing variants in natively expressing pulmonary epithelial cells. J Cyst Fibros. 2019 Jul;18(4):476–483.
  • Park JK, Shrivastava A, Zhang C, et al. Functional profiling of cftr-directed therapeutics using pediatric patient-derived nasal epithelial cell models. Front Pediatr. 2020;8:536.
  • Laselva O, Bartlett C, Popa A, et al. Emerging preclinical modulators developed for F508del-CFTR have the potential to be effective for ORKAMBI resistant processing mutants. J Cyst Fibros. 2021;20(1):106–119.
  • McCravy MS, Quinney NL, Cholon DM, et al. Personalised medicine for non-classic cystic fibrosis resulting from rare CFTR mutations. Eur Respir J. 2020 Jul;56(1):1.
  • Pranke I, Hatton A, Masson A, et al. Might brushed nasal cells be a surrogate for CFTR modulator clinical response? Am J Respir Crit Care Med. 2019 Jan 1;199(1):123–126.
  • Pranke IM, Hatton A, Simonin J, et al. Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators. Sci Rep. 2017 Aug 7;7(1):7375.
  • Guimbellot JS, Leach JM, Chaudhry IG, et al. Nasospheroids permit measurements of CFTR-dependent fluid transport. JCI Insight. 2017 Nov 16;2(22):22.
  • Liu Z, Anderson JD, Deng L, et al. Human Nasal Epithelial Organoids for Therapeutic Development in Cystic Fibrosis. Genes (Basel). 2020 May 29;11(6):6.
  • Brewington JJ, Filbrandt ET, LaRosa FJ 3rd, et al. Detection of CFTR function and modulation in primary human nasal cell spheroids. J Cyst Fibros. 2018 Jan;17(1):26–33.
  • Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009 May 14;459(7244):262–265.
  • Sato T, Stange DE, Ferrante M, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology. 2011 Nov;141(5):1762–1772.
  • Berkers G, Van Mourik P, Vonk AM, et al. Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis. Cell Rep. 2019 Feb 12;26(7):1701–1708. e3.
  • De Winter-de Groot KM, Berkers G, Marck-van Der Wilt REP, et al. Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations. J Cyst Fibros. 2020 Jul;19(4):614–619.
  • Simsek S, Zhou T, Robinson CL, et al. Modeling cystic fibrosis using pluripotent stem cell-derived human pancreatic ductal epithelial cells. Stem Cells Transl Med. 2016 5; May(5): 572–579.
  • Sampaziotis F, De Brito MC, Madrigal P, et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat Biotechnol. 2015 Aug;33(8):845–852.
  • Ogawa M, Ogawa S, Bear CE, et al. Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat Biotechnol. 2015 Aug;33(8):853–861.
  • Mithal A, Capilla A, Heinze D, et al. Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells. Nat Commun. 2020 Jan 10;11(1):215.
  • Litvack ML, Wigle TJ, Lee J, et al. Alveolar-like Stem Cell-derived Myb(-) Macrophages Promote Recovery and Survival in Airway Disease. Am J Respir Crit Care Med. 2016 Jun 1;193(11):1219–1229.
  • Ackermann M, Kempf H, Hetzel M, et al. Bioreactor-based mass production of human iPSC-derived macrophages enables immunotherapies against bacterial airway infections. Nat Commun. 2018 Nov 30;9(1):5088.
  • Wong AP, Bear CE, Chin S, et al. Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nat Biotechnol. 2012 Sep;30(9):876–882.
  • Firth AL, Dargitz CT, Qualls SJ, et al. Generation of multiciliated cells in functional airway epithelia from human induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):E1723–30.
  • Dye BR, Hill DR, Ferguson MA, et al. In vitro generation of human pluripotent stem cell derived lung organoids. Elife. 2015 Mar 24;4. 10.7554/eLife.05098
  • Hawkins FJ, Suzuki S, Beermann ML, et al. Derivation of airway basal stem cells from human pluripotent stem cells. Cell Stem Cell. 2020 Oct 19;28(1):79–95.e8.
  • Merkert S, Schubert M, Olmer R, et al. High-throughput screening for modulators of cftr activity based on genetically engineered cystic fibrosis disease-specific iPSCs. Stem Cell Reports. 2019 Jun 11;12(6):1389–1403.
  • Berical A, Lee RE, Randell SH, et al. challenges facing airway epithelial cell-based therapy for cystic fibrosis. Front Pharmacol. 2019;10:74.
  • Conese M, Beccia E, Castellani S, et al. The long and winding road: stem cells for cystic fibrosis. Expert Opin Biol Ther. 2018 Mar;18(3):281–292.
  • Kim MD, Baumlin N, Yoshida M, et al. Losartan Rescues Inflammation-related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis. Am J Respir Crit Care Med. 2020 Feb 1;201(3):313–324.
  • Rayner RE, Wellmerling J, Osman W, et al. In vitro 3D culture lung model from expanded primary cystic fibrosis human airway cells. J Cyst Fibros. 2020 Sep;19(5):752–761.
  • Boucher RC. An overview of the pathogenesis of cystic fibrosis lung disease. Adv Drug Deliv Rev. 2002 Dec 5;54(11):1359–1371.
  • Simonin J, Bille E, Crambert G, et al. Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis. Sci Rep. 2019 Apr 24;9(1):6516.
  • Coakley RD, Grubb BR, Paradiso AM, et al. Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):16083–16088.
  • Freedman SD, Blanco PG, Zaman MM, et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med. 2004 Feb 5;350(6):560–569.
  • Garic D, De Sanctis JB, Wojewodka G, et al. Fenretinide differentially modulates the levels of long- and very long-chain ceramides by downregulating Cers5 enzyme: evidence from bench to bedside. J Mol Med (Berl). 2017 Oct;95(10):1053–1064.
  • Ernst WL, Shome K, Wu CC, et al. VAMP-associated Proteins (VAP) as receptors that couple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) proteostasis with lipid homeostasis. J Biol Chem. 2016 Mar 4;291(10):5206–5220.
  • Gianotti A, Capurro V, Scudieri P, et al. Pharmacological rescue of mutant CFTR protein improves the viscoelastic properties of CF mucus. J Cyst Fibros. 2016 May;15(3):295–301.
  • Chioccioli M, Feriani L, Kotar J, et al. Phenotyping ciliary dynamics and coordination in response to CFTR-modulators in Cystic Fibrosis respiratory epithelial cells. Nat Commun. 2019 Apr 16;10(1):1763.
  • Choi HC, Kim CS, Tarran R. Automated acquisition and analysis of airway surface liquid height by confocal microscopy. Am J Physiol Lung Cell Mol Physiol. 2015 Jul 15;309(2):L109–18.
  • Song Y, Namkung W, Nielson DW, et al. Airway surface liquid depth measured in ex vivo fragments of pig and human trachea: dependence on Na+ and Cl- channel function. Am J Physiol Lung Cell Mol Physiol. 2009 Dec;297(6):L1131–40.
  • Thiagarajah JR, Song Y, Derichs N, et al. Airway surface liquid depth imaged by surface laser reflectance microscopy. J Gen Physiol. 2010 Sep;136(3):353–362.
  • Pedemonte N, Bertozzi F, Caci E, et al. Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel. Sci Adv. 2020 Feb;6(8):eaay9669.
  • Liessi N, Pesce E, Braccia C, et al. Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta. JCI Insight. 2020 Aug 20;5(16):16.
  • Garic D, De Sanctis JB, Shah J, et al. Biochemistry of very-long-chain and long-chain ceramides in cystic fibrosis and other diseases: The importance of side chain. Prog Lipid Res. 2019 Aug;21:100998.
  • Lipuma JJ. The changing microbial epidemiology in cystic fibrosis. Clin Microbiol Rev. 2010 Apr;23(2):299–323.
  • Saint-Criq V, Villeret B, Bastaert F, et al. Pseudomonas aeruginosa LasB protease impairs innate immunity in mice and humans by targeting a lung epithelial cystic fibrosis transmembrane regulator-IL-6-antimicrobial-repair pathway. Thorax. 2018 Jan;73(1):49–61.
  • Maille E, Ruffin M, Adam D, et al. Quorum sensing down-regulation counteracts the negative impact of pseudomonas aeruginosa on CFTR channel expression, function and rescue in human airway epithelial cells. Front Cell Infect Microbiol. 2017;7:470.
  • MacEachran DP, Ye S, Bomberger JM, et al. The Pseudomonas aeruginosa secreted protein PA2934 decreases apical membrane expression of the cystic fibrosis transmembrane conductance regulator. Infect Immun. 2007 Aug;75(8):3902–3912.
  • Bomberger JM, Ye S, Maceachran DP, et al. A Pseudomonas aeruginosa toxin that hijacks the host ubiquitin proteolytic system. PLoS Pathog. 2011 Mar;7(3):e1001325.
  • Downey DG, Bell SC, Elborn JS. Neutrophils in cystic fibrosis. Thorax. 2009 Jan;64(1):81–88.
  • Laval J, Ralhan A, Hartl D. Neutrophils in cystic fibrosis. Biol Chem. 2016 Feb;397(6):485-96.
  • Nichols DP, Chmiel JF. Inflammation and its genesis in cystic fibrosis. Pediatr Pulmonol. 2015 Oct;50(Suppl 40):S39–56.
  • Twigg MS, Brockbank S, Lowry P, et al. The role of serine proteases and antiproteases in the cystic fibrosis lung. Mediators Inflamm. 2015;2015:293053.
  • Birrer P, McElvaney NG, Rudeberg A, et al. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med. 1994 Jul;150(1):207–213.
  • Devaney JM, Greene CM, Taggart CC, et al. Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 4. FEBS Lett. 2003 Jun 5;544(1–3):129–132.
  • Nakamura H, Yoshimura K, McElvaney NG, et al. Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. J Clin Invest. 1992 May;89(5):1478–1484.
  • Shao MX, Nadel JA. Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme. J Immunol. 2005 Sep 15;175(6):4009–4016.
  • Park JA, He F, Martin LD, et al. Human neutrophil elastase induces hypersecretion of mucin from well-differentiated human bronchial epithelial cells in vitro via a protein kinase C{delta}-mediated mechanism. Am J Pathol. 2005 Sep;167(3):651–661.
  • Weldon S, McNally P, McElvaney NG, et al. Decreased levels of secretory leucoprotease inhibitor in the Pseudomonas-infected cystic fibrosis lung are due to neutrophil elastase degradation. J Immunol. 2009 Dec 15;183(12):8148–8156.
  • Le Gars M, Descamps D, Roussel D, et al. Neutrophil elastase degrades cystic fibrosis transmembrane conductance regulator via calpains and disables channel function in vitro and in vivo. Am J Respir Crit Care Med. 2013 Jan 15;187(2):170–179.
  • Sagel SD, Sontag MK, Wagener JS, et al. Induced sputum inflammatory measures correlate with lung function in children with cystic fibrosis. J Pediatr. 2002 Dec;141(6):811–817.
  • Margaroli C, Garratt LW, Horati H, et al. Elastase exocytosis by airway neutrophils is associated with early lung damage in children with cystic fibrosis. Am J Respir Crit Care Med. 2019 Apr 1;199(7):873–881.
  • Hayes E, Pohl K, McElvaney NG, et al. The cystic fibrosis neutrophil: a specialized yet potentially defective cell. Arch Immunol Ther Exp (Warsz). 2011 Apr;59(2):97–112.
  • Pohl K, Hayes E, Keenan J, et al. A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy. Blood. 2014 Aug 14;124(7):999–1009.
  • Painter RG, Valentine VG, Lanson NA Jr., et al. CFTR expression in human neutrophils and the phagolysosomal chlorination defect in cystic fibrosis. Biochemistry. 2006 Aug 29;45(34):10260–10269.
  • Painter RG, Marrero L, Lombard GA, et al. CFTR-mediated halide transport in phagosomes of human neutrophils. J Leukoc Biol. 2010 May;87(5):933–942.
  • Sun H, Harris WT, Kortyka S, et al. Tgf-beta downregulation of distinct chloride channels in cystic fibrosis-affected epithelia. PLoS One. 2014;9(9):e106842.
  • Snodgrass SM, Cihil KM, Cornuet PK, et al. Tgf-beta1 inhibits Cftr biogenesis and prevents functional rescue of DeltaF508-Cftr in primary differentiated human bronchial epithelial cells. PLoS One. 2013;8(5):e63167.
  • Yi S, Pierucci-Alves F, Schultz BD. Transforming growth factor-beta1 impairs CFTR-mediated anion secretion across cultured porcine vas deferens epithelial monolayer via the p38 MAPK pathway. Am J Physiol Cell Physiol. 2013 Oct 15;305(8):C867–76.
  • Galietta LJ, Folli C, Marchetti C, et al. Modification of transepithelial ion transport in human cultured bronchial epithelial cells by interferon-gamma. Am J Physiol Lung Cell Mol Physiol. 2000 Jun;278(6):L1186–94.
  • Besancon F, Przewlocki G, Baro I, et al. Interferon-gamma downregulates CFTR gene expression in epithelial cells. Am J Physiol. 1994 Nov;267(5 Pt 1):C1398–404.
  • Roux J, McNicholas CM, Carles M, et al. IL-8 inhibits cAMP-stimulated alveolar epithelial fluid transport via a GRK2/PI3K-dependent mechanism. Faseb J. 2013 Mar;27(3):1095–1106.
  • Bebok Z, Varga K, Hicks JK, et al. Reactive oxygen nitrogen species decrease cystic fibrosis transmembrane conductance regulator expression and cAMP-mediated Cl- secretion in airway epithelia. J Biol Chem. 2002 Nov 8;277(45):43041–43049.
  • Schwarzer C, Fischer H, Kim EJ, et al. Oxidative stress caused by pyocyanin impairs CFTR Cl(-) transport in human bronchial epithelial cells. Free Radic Biol Med. 2008 Dec 15;45(12):1653–1662.
  • O’Grady SM. Oxidative stress, autophagy and airway ion transport. Am J Physiol Cell Physiol. 2019 Jan 1;316(1):C16–C32.
  • Stanton BA, Coutermarsh B, Barnaby R, et al. Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells. PLoS One. 2015;10(5):e0127742.
  • Trinh NT, Bilodeau C, Maille E, et al. Deleterious impact of pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells. Eur Respir J. 2015 Jun;45(6):1590–1602.
  • Barnaby R, Koeppen K, Stanton BA. Cyclodextrins reduce the ability of pseudomonas aeruginosa outer-membrane vesicles to reduce CFTR Cl(-) secretion. Am J Physiol Lung Cell Mol Physiol. 2019 Jan 1;316(1):L206–L215.
  • Gentzsch M, Cholon DM, Quinney NL, et al. The cystic fibrosis airway milieu enhances rescue of F508del in a pre-clinical model. Eur Respir J. 2018 Dec;52(6):1801133.
  • Yonker LM, Pazos MA, Lanter BB, et al. Neutrophil-derived cytosolic PLA2alpha contributes to bacterial-induced neutrophil transepithelial migration. J Immunol. 2017 Oct 15;199(8):2873–2884.
  • Yonker LM, Mou H, Chu KK, et al. Development of a Primary Human Co-Culture Model of Inflamed Airway Mucosa. Sci Rep. 2017 Aug 15;7(1):8182.
  • Montefusco-Pereira CV, Horstmann JC, Ebensen T, et al. P. aeruginosa Infected 3D Co-culture of bronchial epithelial cells and macrophages at air-liquid interface for preclinical evaluation of anti-infectives. J Vis Exp. 2020;160. DOI: 10.3791/61069.
  • Benam KH, Villenave R, Lucchesi C, et al. Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro. Nat Methods. 2016 Feb;13(2):151–157.
  • Mejias JC, Nelson MR, Liseth O, et al. A 96-well format microvascularized human lung-on-a-chip platform for microphysiological modeling of fibrotic diseases. Lab Chip. 2020 Sep 29;20(19):3601–3611.
  • Artzy-Schnirman A, Lehr CM, Sznitman J. Advancing human in vitro pulmonary disease models in preclinical research: opportunities for lung-on-chips. Expert Opin Drug Deliv. 2020 May;17(5):621–625.
  • Wilke M, Buijs-Offerman RM, Aarbiou J, et al. Mouse models of cystic fibrosis: phenotypic analysis and research applications. J Cyst Fibros. 2011 Jun;10(Suppl 2):S152–71.
  • Semaniakou A, Croll RP, Chappe V. Animal models in the pathophysiology of cystic fibrosis. Front Pharmacol. 2019 Jan;4(9):1475.
  • Bessanova L, Volkova N, Higgins M, et al. Data from the US and the UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax. 2018 Aug;73(8):731–740.
  • Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: data from national US and UK registries. J Cyst Fibros. 2020 Jan;19(1):68–79.
  • Kirwan L, Fletcher G, Harrington M, et al. Longitudinal trends in real-world outcomes after initiation of ivacaftor. a cohort study from the cystic fibrosis registry of Ireland. Ann Am Thorac Soc. 2019 Feb;16(2):209–216.
  • Sawicki GS, McKone EF, Pasta DJ, et al. Sustained Benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data. Am J Respir Crit Care Med. 2015 Oct 1;192(7):836–842.
  • Heltshe SL, Mayer-Hamblett N, Burns JL, et al. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis. 2015 Mar 1;60(5):703–712.
  • Lopes-Pacheco M, Pedemonte N, Kicic A. Editorial: emerging therapeutic approaches for cystic fibrosis. Front Pharmacol. 2019;10:1440.
  • Moore PJ, Tarran R. The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis lung disease. Expert Opin Ther Targets. 2018 Aug;22:687-701.
  • Li H, Salomon JJ, Sheppard DN, et al. Bypassing CFTR dysfunction in cystic fibrosis with alternative pathways for anion transport. Curr Opin Pharmacol. 2017 Jun;34:91–97.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.