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Perspective

The revolution of personalized pharmacotherapies for cystic fibrosis: what does the future hold?

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 1545-1565 | Received 17 Apr 2023, Accepted 23 Jun 2023, Published online: 03 Jul 2023

References

  • Guo J, Garratt A, Hill A. Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J Cyst Fibros. 2022;21(3):456–462. doi: 10.1016/j.jcf.2022.01.009.
  • Lopes-Pacheco M. CFTR modulators: the changing face of cystic fibrosis in the era of precision medicine. Front Pharmacol. 2020;10:1662. doi: 10.3389/fphar.2019.01662
  • Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989;245:1059–1065. DOI:10.1126/science.2772657
  • Riordan JR, Rommens JM, Kerem BS, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245:1066–1073. DOI:10.1126/science.2475911
  • Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989;245(4922):1073–1080. doi: 10.1126/science.2570460
  • Saint-Criq V, Gray MA. Role of CFTR in epithelial physiology. Cell Mol Life Sci. 2017;74(1):93–115. doi: 10.1007/s00018-016-2391-y
  • Lopes-Pacheco M. CFTR modulators: shedding light on precision medicine for cystic fibrosis. Front Pharmacol. 2016;7:275. doi: 10.3389/fphar.2016.00275
  • Liu F, Zhang Z, Csanády L, et al. Molecular structure of the human CFTR ion channel. Cell. 2017;169(1):85–95.e8. doi: 10.1016/j.cell.2017.02.024
  • Csanády L, Vergani P, Gadsby DC. Structure, gating, and regulation of the CFTR anion channel. Physiol Rev. 2019;99(1):707–738. doi: 10.1152/physrev.00007.2018
  • Kim SJ, Skach WR. Mechanisms of CFTR folding at the endoplasmic reticulum. Front Pharmacol. 2012;3:201. doi: 10.3389/fphar.2012.00201
  • Zhang Z, Liu F, Chen J. Molecular structure of the ATP-bound, phosphorylated human CFTR. Proc Natl Acad Sci U S A. 2018;115(50):12757–12762. doi: 10.1073/pnas.1815287115
  • Cystic Fibrosis Mutation Database (CFTR1 Database) [Internet]. Available from: http://www.genet.sickkids.on.ca/.
  • Clinical and Function Translation of CFTR (CFTR2 Database) [Internet]. Available from: https://cftr2.org/.
  • Marson FAL, Bertuzzo CS, Ribeiro JD. Classification of CFTR mutation classes. Lancet Respir Med. 2016;4(8):e37–e38. doi: 10.1016/S2213-2600(16)30188-6
  • Ensinck MM, Carlon MS. One size does not fit all: the past, present and future of cystic fibrosis causal therapies. Cells. 2022;11(12):1868. doi: 10.3390/cells11121868
  • Southern KW, Castellani C, Lammertyn E, et al. Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis. J Cyst Fibros. 2023;22(1):17–30. doi: 10.1016/j.jcf.2022.10.002
  • Narayanan S, Mainz JG, Gala S, et al. Adherence to therapies in cystic fibrosis: a targeted literature review. Expert Rev Respir Med. 2017;11(2):129–145. InternetAvailable from. doi: http://dx.doi.org/10.1080/17476348.2017.1280399
  • Ramsey BW, Davies JC, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663–1672. doi: 10.1056/NEJMoa1105185
  • Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220–231. doi: 10.1056/NEJMoa1409547
  • Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377(21):2013–2023. doi: 10.1056/NEJMoa1709846
  • Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor–ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21):2024–2035. doi: 10.1056/NEJMoa1709847
  • 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;394(10212):1940–1948. doi: 10.1016/S0140-6736(19)32597-8
  • Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del Allele. N Engl J Med. 2019;381:p. 1809–1819.
  • Bacalhau M, Camargo M, Magalhães-Ghiotto GAV, et al. Elexacaftor-tezacaftor-ivacaftor: a life-changing triple combination of CFTR modulator drugs for cystic fibrosis. Pharmaceuticals. 2023;16(3):410. doi: 10.3390/ph16030410
  • Lopes-Pacheco M, Pedemonte N, Veit G. Discovery of CFTR modulators for the treatment of cystic fibrosis. Expert Opin Drug Discov. 2021;16(8):897–913. doi: 10.1080/17460441.2021.1912732
  • Silva IAL, Laselva O, Lopes-Pacheco M. Advances in preclinical in vitro models for the translation of precision medicine for cystic fibrosis. J Pers Med. 2022;12(8):1321. doi: 10.3390/jpm12081321
  • Okiyoneda T, Veit G, Dekkers JF, et al. Mechanism-based corrector combination restores ΔF508-CFTR folding and function. Nat Chem Biol. 2013;9(7):444–454. doi: 10.1038/nchembio.1253
  • Van Goor F, Hadida S, Grootenhuis PDJ, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A. 2011;108(46):18843–18848. doi: 10.1073/pnas.1105787108
  • Veit G, Avramescu RG, Perdomo D, et al. Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression. Sci Transl Med. 2014;6(246):246ra97. doi: 10.1126/scitranslmed.3008889
  • Lopes-Pacheco M, Boinot C, Sabirzhanova I, et al. Combination of correctors rescue ΔF508-CFTR by reducing its association with Hsp40 and Hsp27. J Biol Chem. 2015;290(42):25636–25645. doi: 10.1074/jbc.M115.671925
  • 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;20(7):943–955. doi: 10.1016/j.chembiol.2013.06.004
  • 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;180:114133. DOI:10.1016/j.bcp.2020.114133
  • 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;24(19):3016–3024. doi: 10.1091/mbc.e13-05-0240
  • Loo TW, Bartlett MC, Clarke DM. Corrector VX-809 stabilizes the first transmembrane domain of CFTR. Biochem Pharmacol. 2013;86(5):612–619. doi: 10.1016/j.bcp.2013.06.028
  • Krainer G, Schenkel M, Hartmann A, et al. CFTR transmembrane segments are impaired in their conformational adaptability by a pathogenic loop mutation and dynamically stabilized by Lumacaftor. J Biol Chem. 2020;295(7):1985–1991. doi: 10.1074/jbc.AC119.011360
  • He L, Kota P, Aleksandrov AA, et al. Correctors of ΔF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein. Faseb J. 2013;27(2):536–545. doi: 10.1096/fj.12-216119
  • Fiedorczuk K, Chen J. Mechanism of CFTR correction by type I folding correctors. Cell. 2022;185(1):158–168.e11. doi: 10.1016/j.cell.2021.12.009
  • Veit G, Xu H, Dreano E, et al. Structure-guided combination therapy to potently improve the function of mutant CFTRs. Nat Med. 2018;24(11):1732–1742. Internet. doi: 10.1038/s41591-018-0200-x
  • 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;5(18):e139983. doi: 10.1172/jci.insight.139983
  • Lopes-Pacheco M, Ferreira FC, Bacalhau M. ePS6.01 Characterisation of F508del-CFTR rescue by corrector PTI-801. J Cyst Fibros. 2022;21:S58. doi: 10.1016/S1569-1993(22)00328-9
  • Bacalhau M, Ferreira FC, Kmit A, et al. Identification of novel F508del-CFTR traffic correctors among triazole derivatives. Eur J Pharmacol. 2023;938:175396. DOI:10.1016/j.ejphar.2022.175396
  • Singh AK, Fan Y, Balut C, et al. Biological characterization of F508DelCFTR protein processing by the CFTR corrector ABBV-2222/GLPG2222. J Pharmacol Exp Ther. 2020;372(1):107–118. doi: 10.1124/jpet.119.261800
  • Bell SC, Barry PJ, De Boeck K, et al. CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials. J Cyst Fibros. 2019;18(5):700–707. doi: 10.1016/j.jcf.2019.04.014
  • Pedemonte N, Bertozzi F, Caci E, et al. Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel. Sci Adv. 2020;6(8):eaay9669. doi: 10.1126/sciadv.aay9669
  • Pedemonte N, Lukacs GL, Du K, et al. Small-molecule correctors of defective F508-CFTR cellular processing identified by high-throughput screening. J Clin Invest. 2005;115(9):2564–2571. doi: 10.1172/JCI24898
  • Lopes-Pacheco M, Sabirzhanova I, Rapino D, et al. Correctors rescue CFTR mutations in nucleotide-binding domain 1 (NBD1) by modulating proteostasis. Chembiochem. 2016;17(6):493–505. doi: 10.1002/cbic.201500620
  • 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. doi: 10.1159/000475578
  • Wang Y, Loo TW, Bartlett MC, et al. Correctors promote maturation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-processing mutants by binding to the protein. J Biol Chem. 2007;282(46):33247–33251. doi: 10.1074/jbc.C700175200
  • Laselva O, Molinski S, Casavola V, et al. Correctors of the major cystic fibrosis mutant interact through membrane-spanning domains. Mol Pharmacol. 2018;93(6):612–618. doi: 10.1124/mol.118.111799
  • Pesce E, Bellotti M, Liessi N, et al. Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis. Eur J Med Chem [InternetAvailable from]. 2015;99:14–35. doi: 10.1016/j.ejmech.2015.05.030
  • Capurro V, Tomati V, Sondo E, et al. Partial rescue of f508del-cftr stability and trafficking defects by double corrector treatment. Int J Mol Sci. 2021;22(10):5262. doi: 10.3390/ijms22105262
  • Baatallah N, Elbahnsi A, Mornon J-P, et al. Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR. Cell Mol Life Sci. 2021;78(23):7813–7829. Internet. doi: 10.1007/s00018-021-03994-5
  • Davies JC, Moskowitz SM, Brown C, et al. VX-659–Tezacaftor–Ivacaftor in patients with cystic fibrosis and one or two Phe508del Alleles. N Engl J Med. 2018;379(17):1599–1611. doi: 10.1056/NEJMoa1807119
  • Fiedorczuk K, Chen J. Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators. Science. 2022;378(6617):284–290. doi: 10.1126/science.ade2216.
  • Im J, Hillenaar T, Yeoh HY, et al. ABC-transporter CFTR folds with high fidelity through a modular, stepwise pathway. Cell Mol Life Sci. 2023;80(1):33. doi: 10.1007/s00018-022-04671-x
  • Uluer AZ, MacGregor G, Azevedo P, et al. Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials. Lancet Respir Med. 2023;11(6):550–562. doi: 10.1016/S2213-2600(22)00504-5
  • Lopes-Pacheco M, Bacalhau M, Ramalho SS, et al. Rescue of mutant CFTR trafficking defect by the investigational compound MCG1516A. Cells. 2022;11(1):136. doi: 10.3390/cells11010136
  • De Wilde G, Gees M, Musch S, et al. Identification of GLPG/ABBV-2737, a novel class of corrector, which exerts functional synergy with other CFTR modulators. Front Pharmacol. 2019;10:514. DOI:10.3389/fphar.2019.00514
  • Scanio MJC, Searle XB, Liu B, et al. Discovery of ABBV/GLPG-3221, a potent corrector of CFTR for the treatment of cystic fibrosis. ACS Med Chem Lett. 2019;10(11):1543–1548. doi: 10.1021/acsmedchemlett.9b00377
  • Greszler SN, Zhao G, Shelat B, et al. Enabling asymmetric synthesis of ABBV-3748, a corrector compound for the treatment of cystic fibrosis. Org Lett. 2022;24(40):7305–7308. doi: 10.1021/acs.orglett.2c02729
  • Hurlbut G, Altmann S, Barrague M, et al. 662 Novel cystic fibrosis transmembrane conductance regulator modulator combinations that address the first nucleotide binding domain defect central to ΔF508 dysfunction enable full correction of cystic fibrosis transmembrane conductance regulator. J Cyst Fibros. 2022;21:S362–S363. DOI:10.1016/S1569-1993(22)01352-2
  • Van Goor F, Hadida S, Grootenhuis PDJ, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009;106(44):18825–18830. doi: 10.1073/pnas.0904709106
  • Eckford PDW, Li C, Ramjeesingh M, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem. 2012;287(44):36639–36649. doi: 10.1074/jbc.M112.393637
  • Jih KY, Hwang TC. Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Proc Natl Acad Sci U S A. 2013;110(11):4404–4409. doi: 10.1073/pnas.1215982110
  • 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. 2021;57(6):2002774. doi: 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;20(5):895–898. doi: 10.1016/j.jcf.2021.03.011 InternetAvailable from.
  • CFF - Drug Development Pipeline [Internet]. Available from: https://apps.cff.org/trials/pipeline/.
  • Harbeson SL, Morgan AJ, Liu JF, et al. Altering metabolic profiles of drugs by precision deuteration 2: discovery of a deuterated analog of ivacaftor with differentiated pharmacokinetics for clinical development. J Pharmacol Exp Ther. 2017;362(2):359–367. doi: 10.1124/jpet.117.241497
  • Gees M, Musch S, Van Der Plas S, et al. Identification and characterization of novel CFTR potentiators. Front Pharmacol. 2018;9:1221. DOI:10.3389/fphar.2018.01221
  • Van Der Plas SE, Kelgtermans H, Mammoliti O, et al. Discovery of GLPG2451, a novel once daily potentiator for the treatment of cystic fibrosis. J Med Chem. 2021;64(1):343–353. doi: 10.1021/acs.jmedchem.0c01796
  • Veit G, Da Fonte DF, Avramescu RG, et al. Mutation-specific dual potentiators maximize rescue of CFTR gating mutants. J Cyst Fibros. 2020;19(2):236–244. doi: 10.1016/j.jcf.2019.10.011
  • Yeh H-I, Qiu L, Sohma Y, et al. Identifying the molecular target sites for CFTR potentiators GLPG1837 and VX-770. J Gen Physiol. 2019;151(7):912–928. doi: 10.1085/jgp.201912360
  • Liu F, Zhang Z, Levit A, et al. Structural identification of a hotspot on CFTR for potentiation. Science. 2019;364(6446):1184–1188. doi: 10.1126/science.aaw7611
  • Grand DL, Gosling M, Baettig U, et al. Discovery of icenticaftor (QBW251), a cystic fibrosis transmembrane conductance regulator potentiator with clinical efficacy in cystic fibrosis and chronic obstructive pulmonary disease. J Med Chem. 2021;64(11):7241–7260. doi: 10.1021/acs.jmedchem.1c00343
  • Cholon D, Aleksandrov L, Quinney N, et al. 647 potentiator icenticaftor is superior to ivacaftor in rescuing F508del cystic fibrosis transmembrane conductance regulator and does not destabilize corrected mature protein. J Cyst Fibros. 2022;21:S355. DOI:10.1016/S1569-1993(22)01337-6
  • Cholon DM, Quinney NL, Fulcher ML, et al. Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis. Sci Transl Med. 2014;6(246):246ra96. doi: 10.1126/scitranslmed.3008680
  • Moran O, Zegarra-Moran O. A quantitative description of the activation and inhibition of CFTR by potentiators: genistein. FEBS Lett. 2005;579(18):3979–3983. doi: 10.1016/j.febslet.2005.06.026
  • 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 [InternetAvailable from]. 2018;17:595–606. doi: 10.1016/j.jcf.2018.05.010
  • Wang F, Zeltwanger S, Yang IC, et al. Actions of genistein on cystic fibrosis transmembrane conductance regulator channel gating. Evidence for two binding sites with opposite effects. J Gen Physiol. 1998;111(3):477–490. doi: 10.1085/jgp.111.3.477
  • Moran O, Galietta LJV, Zegarra-Moran O. Binding site of activators of the cystic fibrosis transmembrane conductance regulator in the nucleotide binding domains. CMLS, Cell Mol Life Sci. 2005;62(4):446–460. doi: 10.1007/s00018-004-4422-3
  • Liu J, Berg AP, Wang Y, et al. A small molecule CFTR potentiator restores ATP-dependent channel gating to the cystic fibrosis mutant G551D-CFTR. Br J Pharmacol. 2022;179(7):1319–1337. doi: 10.1111/bph.15709
  • Bacalhau M, Ferreira FC, Silva IAL, et al. Additive potentiation of R334W-CFTR function by novel small molecules. J Pers Med. 2023;13(1):102. doi: 10.3390/jpm13010102
  • Downey DG, Fajac I, Flume P, et al. Ws11.5 Evaluation of combinations of the CFTR potentiator dirocaftor, corrector posenacaftor and amplifier nesolicaftor in cystic fibrosis subjects with two copies of the F508del mutation. J Cyst Fibros. 2020;19:S19. DOI:10.1016/S1569-1993(20)30226-5
  • Cole B, Bhatt P, Bailey V, et al. 31 Distinguishing properties of CFTR potentiator FDL176. J Cyst Fibros. 2017;16:S71. DOI:10.1016/S1569-1993(17)30396-X
  • 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;19(1):68–79. doi: 10.1016/j.jcf.2019.05.015
  • 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;9(1):1–12. doi: 10.1038/s41598-019-54158-2
  • Haggie PM, Phuan PW, Tan JA, et al. Correctors and potentiators rescue function of the truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) translation product. J Biol Chem. 2017;292(3):771–785. doi: 10.1074/jbc.M116.764720
  • Ensinck MM, De Keersmaecker L, Ramalho AS, et al. Novel CFTR modulator combinations maximise rescue of G85E and N1303K in rectal organoids. ERJ Open Res. 2022;8(2):00716–02021. doi: 10.1183/23120541.00716-2021
  • Hellen CUT. Translation termination and ribosome recycling in eukaryotes. Cold Spring Harb Perspect Biol. 2018;10(10):a032656. doi: 10.1101/cshperspect.a032656
  • Joazeiro CAP. Mechanisms and functions of ribosome-associated protein quality control. Nat Rev Mol Cell Biol. 2019;20(6):368–383. doi: 10.1038/s41580-019-0118-2
  • Yi Z, Sanjeev M, Singh G. The branched nature of the nonsense-mediated mRNA decay pathway. Trends Genet. 2021;37(2):143–159. doi: 10.1016/j.tig.2020.08.010
  • Powers KT, Szeto J-Y, Schaffitzel C. New insights into no-go, non-stop and nonsense-mediated mRNA decay complexes. Curr Opin Struct Biol. 2020;65:110–118. doi: 10.1016/j.sbi.2020.06.011
  • Oren YS, Pranke IM, Kerem B, et al. The suppression of premature termination codons and the repair of splicing mutations in CFTR. Curr Opin Pharmacol. 2017;34:125–131. DOI:10.1016/j.coph.2017.09.017
  • Sharma N, Evans TA, Pellicore MJ, et al. Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis. PLoS Genet. 2018;14(11):e1007723. doi: 10.1371/journal.pgen.1007723
  • Spelier S, van Doorn EPM, van der Ent CK, et al. Readthrough compounds for nonsense mutations: bridging the translational gap. Trends Mol Med. 2023;29(4):297–314. doi: 10.1016/j.molmed.2023.01.004
  • Shao S, Murray J, Brown A, et al. Decoding Mammalian Ribosome-Mrna states by translational GTPase complexes. Cell. 2016;167(5):1229–1240.e15. doi: 10.1016/j.cell.2016.10.046
  • Pettersen EF, Goddard TD, Huand CC, et al. UCSF Chimera?A visualization system for exploratory research and analysis. J Comput Chem. 2004;25(13):1605–1612. doi: 10.1002/jcc.20084
  • Kerem E, Hirawat S, Armoni S, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet. 2008;372(9640):719–727. doi: 10.1016/S0140-6736(08)61168-X
  • Kerem E, Konstan MW, De Boeck K, et al. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med [InternetAvailable from]. 2014;2:539–547. doi: 10.1016/S2213-2600(14)70100-6
  • Wilhelm JM, Jessop JJ, Pettitt SE. Aminoglycoside antibiotics and eukaryotic protein synthesis: stimulation of errors in the translation of natural messengers in extracts of cultured human cells. Biochemistry. 1978;17(7):1149–1153. doi: 10.1021/bi00600a002
  • Konstan MW, VanDevanter DR, Rowe SM, et al. Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: the international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF). J Cyst Fibros [InternetAvailable from]. 2020;19:595–601. doi: 10.1016/j.jcf.2020.01.007
  • Peabody Lever JE, Mutyam V, Hathorne HY, et al. Ataluren/Ivacaftor combination therapy: two N-of-1 trials in cystic fibrosis patients with nonsense mutations. Pediatr Pulmonol. 2020;55(7):1838–1842. doi: 10.1002/ppul.24764
  • Eloxx pharmaceuticals reports positive topline results from monotherapy arms of Phase 2 clinical trial of ELX-02 in class 1 cystic fibrosis patients [Internet]. Available from: https://investors.eloxxpharma.com/node/11986/pdf.
  • Eloxx pharmaceuticals reports topline results from Phase 2 combination clinical trial of ELX-02 in class 1 cystic fibrosis (CF) patients [Internet]. Available from: https://www.globenewswire.com/newsrelease/2022/09/14/2516392/0/en/Eloxx-PharmaceuticalsReports-Topline-Results-from-Phase-2-Combination-ClinicalTrial-of-ELX-02-in-Class-1-Cystic-Fibrosis-CF-Patients.html.
  • Sharma J, Du M, Wong E, et al. A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion. Nat Commun. 2021;12(1):4358. doi: 10.1038/s41467-021-24575-x
  • Ng MY, Li H, Ghelfi MD, et al. Ataluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms. Proc Natl Acad Sci U S A. 2021;118(2):e2020599118. doi: 10.1073/pnas.2020599118
  • Kingwell K. FDA OKs first in vitro route to expanded approval. Nat Rev Drug Discov. 2017;16(9):591–592. doi: 10.1038/nrd.2017.140.
  • 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 data in Lieu of a clinical trial. Ann Am Thorac Soc. 2018;15(1):1–2. doi: 10.1513/AnnalsATS.201708-668PS
  • Clancy JP, Cotton CU, Donaldson SH, et al. CFTR modulator theratyping: current status, gaps and future directions. J Cyst Fibros. 2019;18(1):22–34. doi: 10.1016/j.jcf.2018.05.004
  • Van Goor F, Straley KS, Cao D, et al. Rescue of ΔF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol - Lung Cell Mol Physiol. 2006;290(6):L1117–L1130. doi: 10.1152/ajplung.00169.2005
  • Randell SH, Fulcher ML, O’Neal W, et al. Primary epithelial cell models for cystic fibrosis research. Methods Mol Biol. 2011;742:285–310.
  • Gentzsch M, Boyles SE, Cheluvaraju C, et al. Pharmacological rescue of conditionally reprogrammed cystic fibrosis bronchial epithelial cells. Am J Respir Cell Mol Biol. 2017;56(5):568–574. doi: 10.1165/rcmb.2016-0276MA
  • Lee RE, Lewis CA, He L, et al. Small-molecule eRf3a degraders rescue CFTR nonsense mutations by promoting premature termination codon readthrough. J Clin Invest. 2022;132(18):e154571. doi: 10.1172/JCI154571
  • Mosler K, Coraux C, Fragaki K, et al. Feasibility of nasal epithelial brushing for the study of airway epithelial functions in CF infants. J Cyst Fibros. 2008;7(1):44–53. doi: 10.1016/j.jcf.2007.04.005
  • Brewington JJ, Filbrandt ET, LaRosa FJ, et al. Brushed nasal epithelial cells are a surrogate for bronchial epithelial CFTR studies. JCI Insight. 3 2018;3(13). doi: 10.1172/jci.insight.99385.
  • Baradaran-Heravi A, Balgi AD, Hosseini-Farahabadi S, et al. Effect of small molecule eRF3 degraders on premature termination codon readthrough. Nucleic Acids Res. 2021;49(7):3692–3708. doi: 10.1093/nar/gkab194
  • Nishiguchi G, Keramatnia F, Min J, et al. Identification of potent, selective, and orally bioavailable small-molecule GSPT1/2 degraders from a focused library of cereblon modulators. J Med Chem. 2021;64(11):7296–7311. doi: 10.1021/acs.jmedchem.0c01313
  • Gopalsamy A, Bennett EM, Shi M, et al. Identification of pyrimidine derivatives as Hsmg-1 inhibitors. Bioorg Med Chem Lett [InternetAvailable from]. 2012;22:6636–6641. doi: 10.1016/j.bmcl.2012.08.107
  • Venturini A, Borrelli A, Musante I, et al. Comprehensive analysis of combinatorial pharmacological treatments to correct nonsense mutations in the cftr gene. Int J Mol Sci. 2021;22(21):11972. doi: 10.3390/ijms222111972
  • Spelier S, de Poel E, Ithakisiou GN, et al. High-throughput functional assay in cystic fibrosis patient-derived organoids allows drug repurposing. ERJ Open Res. 2023;9(1):00495–02022. doi: 10.1183/23120541.00495-2022
  • Mutyam V, Du M, Xue X, et al. Discovery of clinically approved agents that promote suppression of cystic fibrosis transmembrane conductance regulator nonsense mutations. Am J Respir Crit Care Med. 2016;194(9):1092–1103. doi: 10.1164/rccm.201601-0154OC
  • Molinski SV, Ahmadi S, Ip W, et al. O rkambi® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue. EMBO Mol Med. 2017;9(9):1224–1243. doi: 10.15252/emmm.201607137
  • Dukovski D, Villella A, Bastos C, et al. Amplifiers co-translationally enhance CFTR biosynthesis via PCBP1-mediated regulation of CFTR mRNA. J Cyst Fibros. 2020;19(5):733–741. Internet. doi: 10.1016/j.jcf.2020.02.006
  • Giuliano KA, Wachi S, Drew L, et al. Use of a high-throughput phenotypic screening strategy to identify amplifiers, a novel pharmacological class of small molecules that exhibit functional synergy with potentiators and correctors. SLAS Discov. 2018;23(2):111–121. doi: 10.1177/2472555217729790
  • Bengtson C, Silswal N, Baumlin N, et al. The CFTR amplifier nesolicaftor rescues TGF-β1 Inhibition of modulator-Corrected F508del CFTR function. Int J Mol Sci. 2022;23(18):23. doi: 10.3390/ijms231810956
  • Smith E, Dukovski D, Shumate J, et al. Identification of compounds that promote readthrough of premature termination codons in the CFTR. SLAS Discov. 2021;26(2):205–215. doi: 10.1177/2472555220962001
  • Crawford DK, Mullenders J, Pott J, et al. Targeting G542X CFTR nonsense alleles with ELX-02 restores CFTR function in human-derived intestinal organoids. J Cyst Fibros. 2021;20(3):436–442. doi: 10.1016/j.jcf.2021.01.009
  • Keenan MM, Huang L, Jordan NJ, et al. Nonsense-mediated RNA decay pathway inhibition restores expression and function of W1282X CFTR. Am J Respir Cell Mol Biol. 2019;61(3):290–300. doi: 10.1165/rcmb.2018-0316OC
  • Mutyam V, Sharma J, Li Y, et al. Novel correctors and potentiators enhance translational readthrough in CFTR nonsense mutations. Am J Respir Cell Mol Biol. 2021;64(5):604–616. doi: 10.1165/rcmb.2019-0291OC
  • Laselva O, Eckford PD, Bartlett C, et al. Functional rescue of c.3846G>A (W1282X) in patient-derived nasal cultures achieved by inhibition of nonsense mediated decay and protein modulators with complementary mechanisms of action. J Cyst Fibros. 2020;19(5):717–727. doi: 10.1016/j.jcf.2019.12.001
  • Zhou Z, Duerr J, Johannesson B, et al. The ENaC-overexpressing mouse as a model of cystic fibrosis lung disease. J Cyst Fibros. 2011;10(2):S172–82. doi: 10.1016/S1569-1993(11)60021-0
  • Moore PJ, Tarran R. The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis lung disease. Expert Opin Ther Targets. 2018;22(8):687–701. doi: 10.1080/14728222.2018.1501361
  • App EM, King M, Helfesrieder R, et al. Acute and long-term amiloride inhalation in cystic fibrosis lung disease: a rational approach to cystic fibrosis therapy. Am Rev Respir Dis. 1990;141(3):605–612. doi: 10.1164/ajrccm/141.3.605
  • Knowles MR, Church NL, Waltner WE, et al. A pilot study of aerosolized amiloride for the treatment of lung disease in cystic fibrosis. N Engl J Med. 1990;322(17):1189–1194. doi: 10.1056/NEJM199004263221704
  • Scheffer GL, Pijnenborg ACLM, Smit EF, et al. Multidrug resistance related molecules in human and murine lung. J Clin Pathol. 2002;55(5):332–339. doi: 10.1136/jcp.55.5.332
  • Danahay H, Gosling M. TMEM16A: an alternative approach to restoring airway Anion secretion in cystic fibrosis? Int J Mol Sci. 2020;21(7):2386. doi: 10.3390/ijms21072386
  • Danahay H, McCarthy C, Gosling M. ePS1.08 a systematic comparison of the profiles of inhaled ENaC blocker candidates on mucociliary clearance: are we under-dosing in clinical studies? J Cyst Fibros. 2019;18:S41. doi: 10.1016/S1569-1993(19)30247-4
  • Caputo A, Caci E, Ferrera L, et al. TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science. 2008;322(5901):590–594. doi: 10.1126/science.1163518
  • Schroeder BC, Cheng T, Jan YN, et al. Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell. 2008;134(6):1019–1029. doi: 10.1016/j.cell.2008.09.003
  • Yang YD, Cho H, Koo JY, et al. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature. 2008;455(7217):1210–1215. doi: 10.1038/nature07313
  • Scudieri P, Caci E, Bruno S, et al. Association of TMEM16A chloride channel overexpression with airway goblet cell metaplasia. J Physiol. 2012;590(23):6141–6155. doi: 10.1113/jphysiol.2012.240838
  • Gorrieri G, Scudieri P, Caci E, et al. Goblet cell hyperplasia requires high bicarbonate transport to support mucin release. Sci Rep. 2016;6(1):36016. doi: 10.1038/srep36016
  • Galietta LJV. TMEM16A (ANO1) as a therapeutic target in cystic fibrosis. Curr Opin Pharmacol. 2022;64:102206. doi: 10.1016/j.coph.2022.102206
  • Pinto MC, Silva IAL, Figueira MF, et al. Pharmacological modulation of ion channels for the treatment of cystic fibrosis. J Exp Pharmacol. 2021;13:693–723. DOI:10.2147/JEP.S255377
  • Centeio R, Ousingsawat J, Cabrita I, et al. Mucus release and airway constriction by TMEM16A may Worsen pathology in inflammatory lung disease. Int J Mol Sci. 2021;22(15):7852. doi: 10.3390/ijms22157852
  • Kunzelmann K, Ousingsawat J, Cabrita I, et al. TMEM16A in cystic fibrosis: activating or inhibiting? Front Pharmacol. 2019;10:3. DOI:10.3389/fphar.2019.00003
  • Accurso FJ, Moss RB, Wilmott RW, et al. Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function. Am J Respir Crit Care Med. 2011;183(5):627–634. doi: 10.1164/rccm.201008-1267OC
  • Ratjen F, Durham T, Navratil T, et al. Long term effects of denufosol tetrasodium in patients with cystic fibrosis. J Cyst Fibros [InternetAvailable from]. 2012;11:539–549. doi: 10.1016/j.jcf.2012.05.003
  • Moss RB. Pitfalls of drug development: lessons learned from trials of denufosol in cystic fibrosis. J Pediatr. 2013;162:676–680. InternetAvailable from. doi: 10.1016/j.jpeds.2012.11.034
  • Namkung W, Yao Z, Finkbeiner WE, et al. Small‐molecule activators of TMEM16A, a calcium‐activated chloride channel, stimulate epithelial chloride secretion and intestinal contraction. Faseb J. 2011;25(11):4048–4062. doi: 10.1096/fj.11-191627
  • Genovese M, Borrelli A, Venturini A, et al. TRPV4 and purinergic receptor signalling pathways are separately linked in airway epithelia to CFTR and TMEM16A chloride channels. J Physiol. 2019;597(24):5859–5878. doi: 10.1113/JP278784
  • Danahay HL, Lilley S, Fox R, et al. TMEM16A potentiation: a novel therapeutic approach for the treatment of cystic fibrosis. Am J Respir Crit Care Med. 2020;201(8):946–954. doi: 10.1164/rccm.201908-1641OC
  • Rehman T, Thornell IM, Pezzulo AA, et al. TNFα and IL-17 alkalinize airway surface liquid through CFTR and pendrin. Am J Physiol - Cell Physiol. 2020;319(2):C331–C344. doi: 10.1152/ajpcell.00112.2020
  • Pedemonte N, Caci E, Sondo E, et al. Thiocyanate transport in resting and IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels. J Immunol. 2007;178(8):5144–5153. doi: 10.4049/jimmunol.178.8.5144
  • Adams KM, Abraham V, Spielman D, et al. IL-17A induces Pendrin expression and chloride-bicarbonate exchange in human bronchial epithelial cells. PLoS One. 2014;9(8):e103263. doi: 10.1371/journal.pone.0103263
  • Garnett JP, Hickman E, Burrows R, et al. Novel role for pendrin in orchestrating bicarbonate secretion in cystic fibrosis transmembrane conductance regulator (CFTR)-expressing airway serous cells. J Biol Chem. 2011;286(47):41069–41082. doi: 10.1074/jbc.M111.266734
  • Garnett JP, Turner MJ. Controversies surrounding the role of CFTR in airway bicarbonate secretion. J Physiol. 2013;591(9):2241–2242. doi: 10.1113/jphysiol.2013.251199
  • Zajac M, Dreano E, Edwards A, et al. Airway surface liquid pH regulation in airway epithelium current understandings and gaps in knowledge. Int J Mol Sci. 2021;22(7):22. doi: 10.3390/ijms22073384
  • Wang Y, Soyombo AA, Shcheynikov N, et al. Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3− secretion: relevance to cystic fibrosis. Embo J. 2006;25(21):5049–5057. doi: 10.1038/sj.emboj.7601387
  • Simonin J, Bille E, Crambert G, et al. Airway surface liquid acidification initiates host defense abnormalities in cystic fibrosis. Sci Rep. 2019;9(1):6516. doi: 10.1038/s41598-019-42751-4
  • Kim D, Huang J, Billet A, et al. Pendrin mediates bicarbonate secretion and enhances cystic fibrosis transmembrane conductance regulator function in airway surface epithelia. Am J Respir Cell Mol Biol. 2019;60(6):705–716. doi: 10.1165/rcmb.2018-0158OC
  • Lohi H, Kujala M, Makela S, et al. Functional characterization of three novel tissue-specific anion exchangers SLC26A7, -A8, and -A9. J Biol Chem. 2002;277(16):14246–14254. doi: 10.1074/jbc.M111802200
  • Avella M, Loriol C, Boulukos K, et al. SLC26A9 stimulates CFTR expression and function in human bronchial cell lines. J Cell Physiol. 2011;226(1):212–223. doi: 10.1002/jcp.22328
  • Bertrand CA, Zhang R, Pilewski JM, et al. SLC26A9 is a constitutively active, CFTR-regulated anion conductance in human bronchial epithelia. J Gen Physiol. 2009;133(4):421–438. doi: 10.1085/jgp.200810097
  • Li H, Salomon JJ, Sheppard DN, et al. Bypassing CFTR dysfunction in cystic fibrosis with alternative pathways for anion transport. Curr Opin Pharmacol [InternetAvailable from]. 2017;34:91–97. doi: 10.1016/j.coph.2017.10.002
  • Anagnostopoulou P, Riederer B, Duerr J, et al. SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation. J Clin Invest. 2012;122(10):3629–3634. doi: 10.1172/JCI60429
  • Strug LJ, Gonska T, He G, et al. Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics. Hum Mol Genet. 2016;25:4590–4600. DOI:10.1093/hmg/ddw290
  • Chen A-P, Chang M-H, Romero MF. Functional analysis of nonsynonymous single nucleotide polymorphisms in human SLC26A9. Hum Mutat. 2012;33(8):1275–1284. doi: 10.1002/humu.22107
  • Pereira SVN, Ribeiro JD, Bertuzzo CS, et al. Interaction among variants in the SLC gene family (SLC6A14, SLC26A9, SLC11A1, and SLC9A3) and CFTR mutations with clinical markers of cystic fibrosis. Pediatr Pulmonol. 2018;53(7):888–900. doi: 10.1002/ppul.24005
  • Corvol H, Mésinèle J, Douksieh IH, et al. SLC26A9 gene is associated with lung function response to ivacaftor in patients with cystic fibrosis. Front Pharmacol. 2018;9:828. DOI:10.3389/fphar.2018.00828
  • Scudieri P, Musante I, Caci E, et al. Increased expression of ATP12A proton pump in cystic fibrosis airways. JCI Insight. 2018;3(20):e123616. doi: 10.1172/jci.insight.123616
  • 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;100(26):16083–16088. doi: 10.1073/pnas.2634339100
  • Shah VS, Ernst S, Tang XX, et al. Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies. Proc Natl Acad Sci, USA. 2016;113(19):5382–5387. doi: 10.1073/pnas.1604905113
  • Chaudhary N, Weissman D, Whitehead KA. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat Rev Drug Discov. 2021;20:817–838. doi: 10.1038/s41573-021-00283-5
  • Lopes-Pacheco M, Silva PL, Cruz FF, et al. Pathogenesis of multiple organ injury in COVID-19 and potential therapeutic strategies. Front Physiol. 2021;12:593223. DOI:10.3389/fphys.2021.593223
  • Rowe SM, Zuckerman JB, Dorgan D, et al. Inhaled mRNA therapy for treatment of cystic fibrosis: interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study. J Cyst Fibros. 2023. doi:10.1016/j.jcf.2023.04.008.
  • 4D Molecular Therapeutics Interim Clinical Data from the On-going Phase 1/2 Clinical Trial of 4D-710 for Cystic Fibrosis Lung Disease to be Presented at NACFC 2022 [Internet]. Available from: https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4d-molecular-therapeutics-interim-clinical-data-going-phase-12/.
  • Sondhi D, Stiles KM, De BP, et al. Genetic modification of the lung directed toward treatment of human disease. Hum Gene Ther. 2017;28(1):3–84. doi: 10.1089/hum.2016.152
  • Alton EWFW, Boyd AC, Davies JC, et al. Genetic medicines for CF: hype versus reality. Pediatr Pulmonol. 2016;51(S44):S5–S17. doi: 10.1002/ppul.23543
  • Cooney AL, McCray PB, Sinn PL. Cystic fibrosis gene therapy: looking back, looking forward. Genes (Basel). 2018;9(11):538. doi: 10.3390/genes9110538
  • 4D Molecular Therapeutics Announces Interim Clinical Data from Phase 1/2 Clinical Trial of 4D-710 for Cystic Fibrosis Lung Disease at NACFC 2022 [Internet]. Available from: https://www.globenewswire.com/news-release/2022/11/03/2547895/0/en/4D-Molecular-Therapeutics-Announces-Interim-Clinical-Data-from-Phase-1-2-Clinical-Trial-of-4D-710-for-Cystic-Fibrosis-Lung-Disease-at-NACFC-2022.html.
  • Okuda K, Shaffer KM, Ehre C. Mucins and CFTR: their close relationship. Int J Mol Sci. 2022;23(18):10232. doi: 10.3390/ijms231810232
  • Cheng Q, Wei T, Farbiak L, et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nat Nanotech. 2020;15(4):313–320. doi: 10.1038/s41565-020-0669-6
  • Piotrowski-Daspit AS, Barone C, Lin C-Y, et al. In vivo correction of cystic fibrosis mediated by PNA nanoparticles. Sci Adv. 2022;8(40):eabo0522. doi: 10.1126/sciadv.abo0522
  • Montoro DT, Haber AL, Biton M, et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature. 2018;560(7718):319–324. doi: 10.1038/s41586-018-0393-7
  • Plasschaert LW, Žilionis R, Choo-Wing R, et al. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature. 2018;560(7718):377–381. doi: 10.1038/s41586-018-0394-6
  • Okuda K, Dang H, Kobayashi Y, et al. Secretory cells dominate airway CFTR expression and function in human airway superficial epithelia. Am J Respir Crit Care Med. 2021;203(10):1275–1289. doi: 10.1164/rccm.202008-3198OC
  • Carraro G, Langerman J, Sabri S, et al. Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition. Nat Med. 2021;27(5):806–814. InternetAvailable from. doi: http://dx.doi.org/10.1038/s41591-021-01332-7
  • Goldfarbmuren KC, Jackson ND, Sajuthi SP, et al. Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium. Nat Commun. 2020;11(1):2485. doi: 10.1038/s41467-020-16239-z
  • Boon M, Verleden SE, Bosch B, et al. Morphometric Analysis of Explant Lungs in Cystic Fibrosis. Am J Respir Crit Care Med. 2016;193(5):516–526. doi: 10.1164/rccm.201507-1281OC
  • Anzalone AV, Koblan LW, Liu DR. Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 2020;38(7):824–844. doi: 10.1038/s41587-020-0561-9
  • Ensinck M, Mottais A, Detry C, et al. On the corner of models and cure: gene editing in cystic fibrosis. Front Pharmacol. 2021;12:662110. DOI:10.3389/fphar.2021.662110
  • Maule G, Ensinck M, Bulcaen M, et al. Rewriting CFTR to cure cystic fibrosis. Prog Mol Biol Transl Sci. 2021;182:185–224.
  • Urnov FD. Imagine CRISPR cures. Mol Ther. 2021;29(11):3103–3106. doi: 10.1016/j.ymthe.2021.10.019
  • Marquez Loza LI, Cooney AL, Dong Q, et al. Increased CFTR expression and function from an optimized lentiviral vector for cystic fibrosis gene therapy. Mol Ther - Methods Clin Dev. 2021;21:94–106. DOI:10.1016/j.omtm.2021.02.020
  • Alton EWFW, Armstrong DK, Ashby D, et al. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3(9):684–691. doi: 10.1016/S2213-2600(15)00245-3
  • Alton EWFW, Beekman JM, Boyd AC, et al. Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis. Thorax. 2017;72(2):137–147. doi: 10.1136/thoraxjnl-2016-208406
  • Vidović D, Carlon MS, da Cunha MF, et al. Raav-CFTRΔR rescues the cystic fibrosis phenotype in human intestinal organoids and cystic fibrosis mice. Am J Respir Crit Care Med. 2016;193(3):288–298. doi: 10.1164/rccm.201505-0914OC
  • Steines B, Dickey DD, Bergen J, et al. CFTR gene transfer with AAV improves early cystic fibrosis pig phenotypes. JCI Insight. 2016;1(14):e88728. doi: 10.1172/jci.insight.88728
  • Cooney AL, Abou Alaiwa MH, Shah VS, et al. Lentiviral-mediated phenotypic correction of cystic fibrosis pigs. JCI Insight. 2016;1(14):e88730. doi: 10.1172/jci.insight.88730
  • Guan S, Munder A, Hedtfeld S, et al. Self-assembled peptide–poloxamine nanoparticles enable in vitro and in vivo genome restoration for cystic fibrosis. Nat Nanotech. 2019;14(3):287–297. doi: 10.1038/s41565-018-0358-x
  • Vaidyanathan S, Baik R, Chen L, et al. Targeted replacement of full-length CFTR in human airway stem cells by CRISPR-Cas9 for pan-mutation correction in the endogenous locus. Mol Ther. 2022;30(1):223–237. doi: 10.1016/j.ymthe.2021.03.023
  • Haque AKMA, Dewerth A, Antony JS, et al. Chemically modified hCFTR mRnas recuperate lung function in a mouse model of cystic fibrosis. Sci Rep. 2018;8(1):16776. doi: 10.1038/s41598-018-34960-0
  • Kolonko AK, Efing J, González-Espinosa Y, et al. Capsaicin-loaded chitosan nanocapsules for wtCFTR-Mrna delivery to a cystic fibrosis cell line. Biomedicines. 2020;8(9):364. doi: 10.3390/biomedicines8090364
  • Suzuki S, Crane AM, Anirudhan V, et al. Highly efficient gene editing of cystic fibrosis patient-derived airway basal cells results in functional CFTR correction. Mol Ther. 2020;28(7):1684–1695. doi: 10.1016/j.ymthe.2020.04.021
  • Bednarski C, Tomczak K, Vom Hövel B, et al. Targeted Integration of a super-exon into the CFTR locus leads to functional correction of a cystic fibrosis cell line model. PLoS One. 2016;11(8):e0161072. doi: 10.1371/journal.pone.0161072
  • Oren YS, Irony-Tur Sinai M, Golec A, et al. Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation. J Cyst Fibros. 2021;20(5):865–875. doi: 10.1016/j.jcf.2021.06.003
  • Michaels WE, Bridges RJ, Hastings ML. Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells. Nucleic Acids Res. 2020;48:7454–7467.
  • Kim YJ, Sivetz N, Layne J, et al. Exon-skipping antisense oligonucleotides for cystic fibrosis therapy. Proc Natl Acad Sci U S A. 2022;119(3):e2114858118. doi: 10.1073/pnas.2114858118
  • Maule G, Casini A, Montagna C, et al. Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing. Nat Commun. 2019;10(1):3556. doi: 10.1038/s41467-019-11454-9
  • Sanz DJ, Hollywood JA, Scallan MF, et al. Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA. PLoS One. 2017;12(9):e0184009. doi: 10.1371/journal.pone.0184009
  • Lueck JD, Yoon JS, Perales-Puchalt A, et al. Engineered transfer RNAs for suppression of premature termination codons. Nat Commun. 2019;10(1):822. doi: 10.1038/s41467-019-08329-4
  • Ko W, Porter JJ, Sipple MT, et al. Efficient suppression of endogenous CFTR nonsense mutations using anticodon-engineered transfer RNAs. Mol Ther Nucleic Acids. 2022;28:685–701.
  • ReCode therapeutics presents preclinical data using SORT-LNPTM and RNA platforms to rescue CFTR function at the 44th European cystic fibrosis conference (ECFS). Available from: https://recodetx.com/recode-therapeutics-presents-preclinical-data-using-sort-lnptm-and-rna-platforms-to-rescue-cftr-function-at-the-44th-european-cystic-fibrosis-conference-ecfs/.
  • Vaidyanathan S, Salahudeen AA, Sellers ZM, et al. High-efficiency, selection-free gene repair in airway stem cells from cystic fibrosis patients rescues CFTR function in differentiated epithelia. Cell Stem Cell. 2020;26(2):161–171.e4. doi: 10.1016/j.stem.2019.11.002
  • Santos L, Mention K, Cavusoglu-Doran K, et al. Comparison of Cas9 and Cas12a CRISPR editing methods to correct the W1282X-CFTR mutation. J Cyst Fibros. 2022;21(1):181–187. doi: 10.1016/j.jcf.2021.05.014
  • Geurts MH, de Poel E, Amatngalim GD, et al. CRISPR-Based Adenine editors correct nonsense mutations in a cystic fibrosis organoid biobank. Cell Stem Cell. 2020;26(4):503–510.e7. doi: 10.1016/j.stem.2020.01.019
  • Amistadi S, Maule G, Ciciani M, et al. Functional restoration of a CFTR splicing mutation through RNA delivery of CRISPR adenine base editor. Mol Ther. 2023;31(6):1647–1660. doi: 10.1016/j.ymthe.2023.03.004
  • Krishnamurthy S, Traore S, Cooney AL, et al. Functional correction of CFTR mutations in human airway epithelial cells using adenine base editors. Nucleic Acids Res. 2021;49(18):10558–10572. doi: 10.1093/nar/gkab788
  • Geurts MH, de Poel E, Pleguezuelos-Manzano C, et al. Evaluating CRISPR-based prime editing for cancer modeling and CFTR repair in organoids. Life Sci Alliance. 2021;4(10):e202000940. doi: 10.26508/lsa.202000940
  • Schene IF, Joore IP, Baijens JHL, et al. Mutation-specific reporter for optimization and enrichment of prime editing. Nat Commun. 2022;13(1):1028. doi: 10.1038/s41467-022-28656-3
  • Doman JL, Sousa AA, Randolph PB, et al. Designing and executing prime editing experiments in mammalian cells. Nat Protoc. 2022;17(11):2431–2468. doi: 10.1038/s41596-022-00724-4
  • Harrison PT. CFTR RNA- and DNA-based therapies. Curr Opin Pharmacol. 2022;65:102247. doi: 10.1016/j.coph.2022.102247
  • Hodges CA, Conlon RA. Delivering on the promise of gene editing for cystic fibrosisx. Genes Dis. 2019;6(2):97–108. doi: 10.1016/j.gendis.2018.11.005
  • Costa E, Girotti S, Pauro F, et al. The impact of FDA and EMA regulatory decision-making process on the access to CFTR modulators for the treatment of cystic fibrosis. Orphanet J Rare Dis. 2022;17(1):188. doi: 10.1186/s13023-022-02350-5
  • Cystic fibrosis foundation patient registry - 2021 annual data Report [Internet]. Available from: https://www.cff.org/media/9741/download.
  • Zampoli M, Morrow BM, Paul G. Real-world disparities and ethical considerations with access to CFTR modulator drugs: mind the gap! Front Pharmacol. 2023;14:1163391.

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