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Molecular Diagnosis & Therapy

, Volume 23, Issue 2, pp 263–279 | Cite as

Innovative Therapies for Cystic Fibrosis: The Road from Treatment to Cure

  • Giulio CabriniEmail author
Review Article

Abstract

Cystic fibrosis (CF), a life-threatening multiorgan genetic disease, is facing a new era of research and development using innovative gene-directed personalized therapies. The priority organ to cure is the lung, which suffers recurrent and chronic bacterial infection and inflammation since infancy, representing the main cause of morbidity and precocious mortality of these individuals. After the disappointing failure of gene-replacement approaches using gene therapy vectors, no single drug is presently available to repair all the CF gene defects. The impressive number of different CF gene mutations is now tackled with different chemical and biotechnological tools tailored to the specific molecular derangements, thanks to the extensive knowledge acquired over many years on the mechanisms of CF cell and organ pathology. This review provides an overview and recalls both the successes and limitations of the different experimental approaches, such as high-throughput screening on chemical libraries to discover CF gene correctors and potentiators, dual-acting compounds, read-through molecules, splicing defect repairing tools, cystic fibrosis transmembrane conductance regulator (CFTR) “amplifiers,” CFTR interactome modulators and the first gene editing attempts.

Notes

Acknowledgements

The author is grateful to many colleagues in Europe, the USA and Canada, but is strongly in debt to those in his research group, particularly Maria Cristina Dechecchi and Anna Tamanini for daily scientific discussions over many years. This review is dedicated to Rossella Rolfini, who prematurely left her beloved friends and colleagues, leaving us alone with our dream of the final cure for the patients affected by CF.

Compliance with Ethical Standards

Conflict of interest

The author, Giulio Cabrini, declares no conflict of interest. GC is co-inventor, but not owner, of the US patent no. U.S.A. 9.183.206 B2 “Trimethylangelicin as CFTR corrector in bronchial epithelial cells.”

Funding

This review was made possible by the support of different research projects with grants from the Telethon Foundation, CariVerona Foundation and Italian Cystic Fibrosis Research Foundation (FFC no. 17/2010, 1/2011, 5/2011, 1/2012, 1/2013, 8/2014, 17/2014, 9/2015, 1/2016, and 3/2016).

References

  1. 1.
    Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, Durie PR, Legrys VA, Massie J, Parad RB, Rock MJ. PW 3rd; Cystic Fibrosis Foundation. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: cystic Fibrosis Foundation consensus report. J Pediatr. 2008;153:S4–14.Google Scholar
  2. 2.
    Elborn JS. Cystic fibrosis. Lancet. 2016;388:2519–31.Google Scholar
  3. 3.
    Davis PB. Cystic fibrosis since 1938. Am J Respir Crit Care Med. 2006;173:475–82.Google Scholar
  4. 4.
    Chmiel JF, Konstan MW, Elborn JS. Antibiotic and anti-inflammatory therapies for cystic fibrosis. Cold Spring Harb Perspect Med. 2013;3:a009779.Google Scholar
  5. 5.
    Cohen-Cymberknoh M., Shoseyov D, Kerem E. Managing cystic fibrosis. Strategies to increase life expectancy and improve quality of life. Am J respir Crit Care Med 2011;183:1463.Google Scholar
  6. 6.
    Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989;245:1059–65.Google Scholar
  7. 7.
    Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245:1066–73.Google Scholar
  8. 8.
    Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989;245:1073–80.Google Scholar
  9. 9.
    Bell SC, De Boeck K, Amaral MD. New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Pharmacol Ther. 2015;145:19–34.Google Scholar
  10. 10.
    Higgins CF. ABC transporters: from microorganisms to man. Annu Rev Cell Biol. 1992;8:67–113.Google Scholar
  11. 11.
    Trezise AE, Buchwald M. In vivo cell-specific expression of the cystic fibrosis transmembrane conductance regulator. Nature. 1991;353:434–7.Google Scholar
  12. 12.
    Denning GM, Ostedgaard LS, Cheng SH, Smith AE, Welsh MJ. Localization of cystic fibrosis transmembrane conductance regulator in chloride secretory epithelia. J Clin Invest. 1992;89:339–49.Google Scholar
  13. 13.
    Hasegawa H, Skach W, Baker O, Calayag MC, Lingappa V, Verkman AS. A multifunctional aqueous channel formed by CFTR. Science. 1992;258:1477–9.Google Scholar
  14. 14.
    Reisin IL, Prat AG, Abraham EH, Amara JF, Gregory RJ, Ausiello DA. The cystic fibrosis transmembrane conductance regulator is a dual ATP and chloride channel. J Biol Chem. 1994;269:20584–91.Google Scholar
  15. 15.
    Prat AG, Reisin IL, Ausiello DA, Cantiello HF. Cellular ATP release by the cystic fibrosis transmembrane conductance regulator. Am J Physiol. 1996;270:C538–45.Google Scholar
  16. 16.
    Abraham EH, Okunieff P, Scala S, Vos P, Oosterveld MJ, Chen AY, Shrivastav B. Cystic fibrosis transmembrane conductance regulator and adenosine triphosphate. Science. 1997;275:1324–6.Google Scholar
  17. 17.
    Cantiello HF. Nucleotide transport through the cystic fibrosis transmembrane conductance regulator. Biosci Rep. 1997;17:147–71.Google Scholar
  18. 18.
    Boucher RC. Evidence for airway surface dehydration as the initiating event in CF airway disease. J Intern Med. 2007;261:5–16.Google Scholar
  19. 19.
    Shah VS, Meyerholz DK, Tang XX, Reznikov L, Abou Alaiwa M, Ernst SE, Karp PH, Wohlford-Lenane CL, Heilmann KP, Leidinger MR, Allen PD, Zabner J, McCray PB Jr, Ostedgaard LS, Stoltz DA, Randak CO, Welsh MJ. Airway acidification initiates host defense abnormalities in cystic fibrosis mice. Science. 2016;351:503–7.Google Scholar
  20. 20.
    Tang XX, Ostedgaard LS, Hoegger MJ, Moninger TO, Karp PH, McMenimen JD, Choudhury B, Varki A, Stoltz DA, Welsh MJ. Acidic pH increases airway surface liquid viscosity in cystic fibrosis. J Clin Invest. 2016;126:879–91.Google Scholar
  21. 21.
    Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. N Engl J Med. 2015;372:1574–5.Google Scholar
  22. 22.
    Rich DP, Anderson MP, Gregory RJ, Cheng SH, Paul S, Jefferson DM, McCann JD, Klinger KW, Smith AE, Welsh MJ. Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature. 1990;347:358–63.Google Scholar
  23. 23.
    Egan M, Flotte T, Afione S, Solow R, Zeitlin PL, Carter BJ, Guggino WB. Defective regulation of outwardly rectifying Cl- channels by protein kinase A corrected by insertion of CFTR. Nature. 1992;358:581–4.Google Scholar
  24. 24.
    Quinton PM, Reddy MM. Control of CFTR chloride conductance by ATP levels through non-hydrolytic binding. Nature. 1992;360:79–81.Google Scholar
  25. 25.
    Gabriel SE, Clarke LL, Boucher RC, Stutts MJ. CFTR and outward rectifying chloride channels are distinct proteins with a regulatory relationship. Nature. 1993;363:263–8 (PMID: 7683773).Google Scholar
  26. 26.
    Dechecchi MC, Rolfini R, Tamanini A, Gamberi C, Berton G, Cabrini G. Effect of modulation of protein kinase C on the cAMP-dependent chloride conductance in T84 cells. FEBS Lett. 1992;311:25–8.Google Scholar
  27. 27.
    Berger HA, Travis SM, Welsh MJ. Regulation of the cystic fibrosis transmembrane conductance regulator Cl- channel by specific protein kinases and protein phosphatases. J Biol Chem. 1993;268:2037–47.Google Scholar
  28. 28.
    Dechecchi MC, Tamanini A, Berton G, Cabrini G. Protein kinase C activates chloride conductance in C127 cells stably expressing the cystic fibrosis gene. J Biol Chem. 1993;268:11321–5.Google Scholar
  29. 29.
    Zemanick ET, Hoffman LR. Cystic Fibrosis: microbiology and host response. Pediatr Clin North Am. 2016;63:617–36.Google Scholar
  30. 30.
    Cohen TS, Prince A. Cystic fibrosis: a mucosal immunodeficiency syndrome. Nat Med. 2012;18:509–19.Google Scholar
  31. 31.
    Tabary O, Zahm JM, Hinnrasky J, Couetil JP, Cornillet P, Guenounou M, Gaillard D, Puchelle E, Jacquot J. Selective up-regulation of chemokine IL-8 expression in cystic fibrosis bronchial gland cells in vivo and in vitro. Am J Pathol. 1998;153:921–30.Google Scholar
  32. 32.
    Tirouvanziam R, de Bentzmann S, Hubeau C, Hinnrasky J, Jacquot J, Péault B, Puchelle E. Inflammation and infection in naive human cystic fibrosis airway grafts. Am J Respir Cell Mol Biol. 2000;23:121–7.Google Scholar
  33. 33.
    Rosen BH, Evans TIA, Moll SR, Gray JS, Liang B, Sun X, Zhang Y, Jensen-Cody CW, Swatek AM, Zhou W, He N, Rotti PG, Tyler SR, Keiser NW, Anderson PJ, Brooks L, Li Y, Pope RM, Rajput M, Hoffman EA, Wang K, Harris JK, Parekh KR, Gibson-Corley KN, Engelhardt JF. Infection is not required for mucoinflammatory lung disease in CFTR-knockout ferrets. Am J Respir Crit Care Med. 2018;197:1308–18.Google Scholar
  34. 34.
    Galli F, Battistoni A, Gambari R, Pompella A, Bragonzi A, Pilolli F, Iuliano L, Piroddi M, Dechecchi MC, Cabrini G; Working Group on Inflammation in Cystic Fibrosis. Oxidative stress and antioxidant therapy in cystic fibrosis. Biochim Biophys Acta. 2012;1822:690–713.Google Scholar
  35. 35.
    Cabrini G, Bezzerri V, Mancini I, Nicolis E, Dechecchi MC, Tamanini A, Lampronti I, Piccagli L, Bianchi N, Borgatti M, Gambari R. Targeting transcription factor activity as a strategy to inhibit pro-inflammatory genes involved in cystic fibrosis: decoy oligo nucleotides and low-molecular weight compounds. Curr Med Chem. 2010;17:4392–404.Google Scholar
  36. 36.
    Hoenderdos K, Lodge KM, Hirst RA, Chen C, Palazzo SG, Emerenciana A, Summers C, Angyal A, Porter L, Juss JK, O’Callaghan C, Chilvers ER, Condliffe AM. Hypoxia upregulates neutrophil degranulation and potential for tissue injury. Thorax. 2016;71:1030–8.Google Scholar
  37. 37.
    Marcos V, Zhou-Suckow Z, Önder Yildirim A, Bohla A, Hector A, Vitkov L, Krautgartner WD, Stoiber W, Griese M, Eickelberg O, Mall MA, Hartl D. Free DNA in cystic fibrosis airway fluids correlates with airflow obstruction. Mediators Inflamm. 2015;2015:408935.Google Scholar
  38. 38.
    Law SM, Gray RD. Neutrophil extracellular traps and the dysfunctional innate immune response of cystic fibrosis lung disease: a review. J Inflamm (Lond). 2017;14:29.Google Scholar
  39. 39.
    Gray RD, Hardisty G, Regan KH, Smith M, Robb CT, Duffin R, Mackellar A, Felton JM, Paemka L, McCullagh BN, Lucas CD, Dorward DA, McKone EF, Cooke G, Donnelly SC, Singh PK, Stoltz DA, Haslett C, McCray PB, Whyte MKB, Rossi AG, Davidson DJ. Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis. Thorax. 2018;73:134–44.Google Scholar
  40. 40.
    Lynch JP 3rd, Sayah DM, Belperio JA, Weigt SS. Lung transplantation for cystic fibrosis: results, indications, complications, and controversies. Semin Respir Crit Care Med. 2015;36:299–320.Google Scholar
  41. 41.
    Chaparro C, Keshavjee S. Lung transplantation for cystic fibrosis: an update. Expert Rev Respir Med. 2016;10:1269–80.Google Scholar
  42. 42.
    Snell G, Reed A, Stern M, Hadjiliadis D. The evolution of lung transplantation for cystic fibrosis: a 2017 update. J Cyst Fibros. 2017;16:553–64.Google Scholar
  43. 43.
    Fink AK, Yanik EL, Marshall BC, Wilschanski M, Lynch CF, Austin AA, Copeland G, Safaeian M, Engels EA. Cancer risk among lung transplant recipients with cystic fibrosis. J Cyst Fibros. 2017;16:91–7.Google Scholar
  44. 44.
    Lu BR, Esquivel CO. A review of abdominal organ transplantation in cystic fibrosis. Pediatr Transplant. 2010;14:954–60.Google Scholar
  45. 45.
  46. 46.
    Tsui LC, Dorfman R. The cystic fibrosis gene: a molecular genetic perspective. Cold Spring Harb Perspect Med. 2013;3:a009472.Google Scholar
  47. 47.
    Bobadilla JL, Macek M Jr, Fine JP, Farrell PM. Cystic fibrosis: a worldwide analysis of CFTR mutations–correlation with incidence data and application to screening. Hum Mutat. 2002;19:575–606.Google Scholar
  48. 48.
    Mateu E, Calafell F, Lao O, Bonné-Tamir B, Kidd JR, Pakstis A, Kidd KK, Bertranpetit J. Worldwide genetic analysis of the CFTR region. Am J Hum Genet. 2001;68:103–17.Google Scholar
  49. 49.
    Feuillet-Fieux MN, Ferrec M, Gigarel N, Thuillier L, Sermet I, Steffann J, Lenoir G, Bonnefont JP. Novel CFTR mutations in black cystic fibrosis patients. Clin Genet. 2004;65:284–7.Google Scholar
  50. 50.
    Maria Ciminelli B, Bombieri C, Ciccacci C, Belpinati F, Pompei F, Maselli R, Simporé J, Pignatti PF, Modiano G. Anthropological features of the CFTR gene: its variability in an African population. Ann Hum Biol. 2011;38:203–9.Google Scholar
  51. 51.
    Singh M, Rebordosa C, Bernholz J, Sharma N. Epidemiology and genetics of cystic fibrosis in Asia: in preparation for the next-generation treatments. Respirology. 2015;20:1172–81.Google Scholar
  52. 52.
    Schrijver I, Pique L, Graham S, Pearl M, Cherry A, Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing. J Mol Diagn. 2016;18:39–50.Google Scholar
  53. 53.
    Bosch B, Bilton D, Sosnay P, Raraigh KS, Mak DYF, Ishiguro H, Gulmans V, Thomas M, Cuppens H, Amaral M, De Boeck K. Ethnicity impacts the cystic fibrosis diagnosis: a note of caution. J Cyst Fibros. 2017;16:488–91.Google Scholar
  54. 54.
    Zheng B, Cao L. Differences in gene mutations between Chinese and Caucasian cystic fibrosis patients. Pediatr Pulmonol. 2017;52:E11–4.Google Scholar
  55. 55.
    Cheng SH, Gregory RJ, Marshall J, Paul S, Souza DW, White GA, O’Riordan CR, Smith AE. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell. 1990;63:827–34.Google Scholar
  56. 56.
    Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet. 1995;29:777–807.Google Scholar
  57. 57.
    Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med. 2010;363:301–4.Google Scholar
  58. 58.
    Verkman AS, Galietta LJ. Chloride channels as drug targets. Nat Rev Drug Discov. 2009;8:153–71.Google Scholar
  59. 59.
    Illsley NP, Verkman AS. Membrane chloride transport measured using a chloride-sensitive fluorescent probe. Biochemistry. 1987;26:1215–9.Google Scholar
  60. 60.
    Biwersi J, Farah N, Wang YX, Ketcham R, Verkman AS. Synthesis of cell-impermeable Cl-sensitive fluorescent indicators with improved sensitivity and optical properties. Am J Physiol. 1992;262:C242–50.Google Scholar
  61. 61.
    Biwersi J, Tulk B, Verkman AS. Long-wavelength chloride-sensitive fluorescent indicators. Anal Biochem. 1994;219:139–43.Google Scholar
  62. 62.
    Jayaraman S, Biwersi J, Verkman AS. Synthesis and characterization of dual-wavelength Cl-sensitive fluorescent indicators for ratio imaging. Am J Physiol. 1999;276:C747–57.Google Scholar
  63. 63.
    Cabrini G, Verkman AS. Potential-sensitive response mechanism of diS-C3-(5) in biological membranes. J Membr Biol. 1986;92:171–82.Google Scholar
  64. 64.
    Cabrini G, Verkman AS. Localization of cyanine dye binding to brush-border membranes by quenching of n-(9-anthroyloxy) fatty acid probes. Biochim Biophys Acta. 1986;862:285–93.Google Scholar
  65. 65.
    Renier M, Tamanini A, Nicolis E, Rolfini R, Imler JL, Pavirani A, Cabrini G. Use of a membrane potential-sensitive probe to assess biological expression of the cystic fibrosis transmembrane conductance regulator. Hum Gene Ther. 1995;6:1275–83.Google Scholar
  66. 66.
    Van Goor F, Straley KS, Cao D, González J, Hadida S, Hazlewood A, Joubran J, Knapp T, Makings LR, Miller M, Neuberger T, Olson E, Panchenko V, Rader J, Singh A, Stack JH, Tung R, Grootenhuis PD, Negulescu P. Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol Lung Cell Mol Physiol. 2006;290:L1117–30.Google Scholar
  67. 67.
    Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA. 2009;106:18825–30.Google Scholar
  68. 68.
    Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu PA. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA. 2011;108:18843–8.Google Scholar
  69. 69.
    Jayaraman S, Haggie P, Wachter RM, Remington SJ, Verkman AS. Mechanism and cellular applications of a green fluorescent protein-based halide sensor. J Biol Chem. 2000;275:6047–50.Google Scholar
  70. 70.
    Galietta LJ, Haggie PM, Verkman AS. Green fluorescent protein-based halide indicators with improved chloride and iodide affinities. FEBS Lett. 2001;499:220–4.Google Scholar
  71. 71.
    Galietta LV, Jayaraman S, Verkman AS. Cell-based assay for high-throughput quantitative screening of CFTR chloride transport agonists. Am J Physiol Cell Physiol. 2001;281:C1734–42.Google Scholar
  72. 72.
    Galietta LJ, Springsteel MF, Eda M, Niedzinski EJ, By K, Haddadin MJ, Kurth MJ, Nantz MH, Verkman AS. Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds. J Biol Chem. 2001;276:19723–8.Google Scholar
  73. 73.
    Ma T, Vetrivel L, Yang H, Pedemonte N, Zegarra-Moran O, Galietta LJ, Verkman AS. High-affinity activators of cystic fibrosis transmembrane conductance regulator (CFTR) chloride conductance identified by high-throughput screening. J Biol Chem. 2002;277:37235–41.Google Scholar
  74. 74.
    Caci E, Folli C, Zegarra-Moran O, Ma T, Springsteel MF, Sammelson RE, Nantz MH, Kurth MJ, Verkman AS, Galietta LJ. CFTR activation in human bronchial epithelial cells by novel benzoflavone and benzimidazolone compounds. Am J Physiol Lung Cell Mol Physiol. 2003;285:L180–8.Google Scholar
  75. 75.
    Yang H, Shelat AA, Guy RK, Gopinath VS, Ma T, Du K, Lukacs GL, Taddei A, Folli C, Pedemonte N, Galietta LJ, Verkman AS. Nanomolar affinity small molecule correctors of defective Delta F508-CFTR chloride channel gating. J Biol Chem. 2003;278:35079–85.Google Scholar
  76. 76.
    Ma T, Thiagarajah JR, Yang H, Sonawane ND, Folli C, Galietta LJ, Verkman AS. Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. J Clin Invest. 2002;110:1651–8.Google Scholar
  77. 77.
    Wang X, Venable J, LaPointe P, Hutt DM, Koulov AV, Coppinger J, Gurkan C, Kellner W, Matteson J, Plutner H, Riordan JR, Kelly JW, Yates JR 3rd, Balch WE. Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell. 2006;127:803–15.Google Scholar
  78. 78.
    Pankow S, Bamberger C, Calzolari D, Martínez-Bartolomé S, Lavallée-Adam M, Balch WE, Yates JR 3rd. ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature. 2015;528:510–6.Google Scholar
  79. 79.
    Gruenert DC, Basbaum CB, Welsh MJ, Li M, Finkbeiner WE, Nadel JA. Characterization of human tracheal epithelial cells transformed by an origin-defective simian virus 40. Proc Natl Acad Sci USA. 1988;85:5951–5.Google Scholar
  80. 80.
    Gruenert DC, Basbaum CB, Widdicombe JH. Long-term culture of normal and cystic fibrosis epithelial cells grown under serum-free conditions. Vitro Cell Dev Biol. 1990;26:411–8.Google Scholar
  81. 81.
    Zabner J, Karp P, Seiler M, Phillips SL, Mitchell CJ, Saavedra M, Welsh M, Klingelhutz AJ. Development of cystic fibrosis and noncystic fibrosis airway cell lines. Am J Physiol Lung Cell Mol Physiol. 2003;284:L844–54.Google Scholar
  82. 82.
    Bebok Z, Collawn JF, Wakefield J, Parker W, Li Y, Varga K, Sorscher EJ, Clancy JP. Failure of cAMP agonists to activate rescued deltaF508 CFTR in CFBE41o- airway epithelial monolayers. J Physiol. 2005;569:601–15.Google Scholar
  83. 83.
    Rosen BH, Chanson M, Gawenis LR, Liu J, Sofoluwe A, Zoso A, Engelhardt JF. Animal and model systems for studying cystic fibrosis. J Cyst Fibros. 2017;S1569–1993(17):30880–9.Google Scholar
  84. 84.
    Dekkers JF, Wiegerinck CL, de Jonge HR, Bronsveld I, Janssens HM, de Winter-de Groot KM, Brandsma AM, de Jong NW, Bijvelds MJ, Scholte BJ, Nieuwenhuis EE, van den Brink S, Clevers H, van der Ent CK, Middendorp S, Beekman JM. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med. 2013;19:939–45.Google Scholar
  85. 85.
    Noordhoek J, Gulmans V, van der Ent K, Beekman JM. Intestinal organoids and personalized medicine in cystic fibrosis: a successful patient-oriented research collaboration. Curr Opin Pulm Med. 2016;22:610–6.Google Scholar
  86. 86.
    Yan Z, Stewart ZA, Sinn PL, Olsen JC, Hu J, McCray PB Jr, Engelhardt JF. Ferret and pig models of cystic fibrosis: prospects and promise for gene therapy. Hum Gene Ther Clin Dev. 2015;26:38–49.Google Scholar
  87. 87.
    Lavelle GM, White MM, Browne N, McElvaney NG, Reeves EP. Animal models of cystic fibrosis pathology: phenotypic parallels and divergences. Biomed Res Int. 2016;2016:5258727.Google Scholar
  88. 88.
    Yu H, Burton B, Huang CJ, Worley J, Cao D, Johnson JP Jr, Urrutia A, Joubran J, Seepersaud S, Sussky K, Hoffman BJ, Van Goor F. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012;11:237–45.Google Scholar
  89. 89.
    Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363:1991–2003.Google Scholar
  90. 90.
    Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663–72.Google Scholar
  91. 91.
    Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, Mainz JG, Rodriguez S, Li H, Yen K, Ordoñez CL, Ahrens R; VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187:1219–25.Google Scholar
  92. 92.
    Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, Mainz JG, Rodriguez S, Li H, Yen K, Ordoñez CL, Ahrens R; VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187:1219–25.Google Scholar
  93. 93.
    Hebestreit H, Sauer-Heilborn A, Fischer R, Käding M, Mainz JG. Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation. J Cyst Fibros. 2013;12:599–603.Google Scholar
  94. 94.
    Barry PJ, Plant BJ, Nair A, Bicknell S, Simmonds NJ, Bell NJ, Shafi NT, Daniels T, Shelmerdine S, Felton I, Gunaratnam C, Jones AM, Horsley AR. Effects of ivacaftor in patients with cystic fibrosis who carry the G551D mutation and have severe lung disease. Chest. 2014;146:152–8.Google Scholar
  95. 95.
    De Boeck K, Paskavitz J, Chen X, Higgins M. Ivacaftor, a CFTR potentiator, in cystic fibrosis patients who have a nonG551D-CFTR gating mutation: phase 3, part 1 results. Pediatr Pulmonol. 2013;48:S36).Google Scholar
  96. 96.
    De Boeck K, Zolin A, Cuppens H, Olesen HV, Viviani L. The relative frequency of CFTR mutation classes in European patients with cystic fibrosis. J Cyst Fibros. 2014;13:403–9.Google Scholar
  97. 97.
    Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS, Ashlock MA, Ballmann M, Boyle MP, Bronsveld I, Campbell PW, De Boeck K, Donaldson SH, Dorkin HL, Dunitz JM, Durie PR, Jain M, Leonard A, McCoy KS, Moss RB, Pilewski JM, Rosenbluth DB, Rubenstein RC, Schechter MS, Botfield M, Ordoñez CL, Spencer-Green GT, Vernillet L, Wisseh S, Yen K, Konstan MW. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax. 2012;67:12–8.Google Scholar
  98. 98.
    Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, Crystal RG, Pavirani A, Lecocq JP, Lazdunski M. Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature. 1991;354:526–8.Google Scholar
  99. 99.
    Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, Huang X, Waltz D, Patel NR, Rodman D. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet. Respir Med. 2014;2:527–38.Google Scholar
  100. 100.
    Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP. TRANSPORT Study Group. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373:220–31.Google Scholar
  101. 101.
    Rowe SM, McColley SA, Rietschel E, Li X, Bell SC, Konstan MW, Marigowda G, Waltz D, Boyle MP. Lumacaftor/Ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR. Ann Am Thorac Soc. 2017;14:213–9.Google Scholar
  102. 102.
    Cholon DM, Quinney NL, Fulcher ML, Esther CR Jr, Das J, Dokholyan NV, Randell SH, Boucher RC, Gentzsch M. Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis. Sci Transl Med. 2014;6:246ra96.Google Scholar
  103. 103.
    Veit G, Avramescu RG, Perdomo D, Phuan PW, Bagdany M, Apaja PM, Borot F, Szollosi D, Wu YS, Finkbeiner WE. Hegedus T, Verkman AS, Lukacs GL. Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression. Sci Transl Med. 2014;6:246ra97.Google Scholar
  104. 104.
    Hanrahan JW, Matthes E, Carlile G, Thomas DY. Corrector combination therapies for F508del-CFTR. Curr Opin Pharmacol. 2017;34:105–11.Google Scholar
  105. 105.
    Howard M, Frizzell RA, Bedwell DM. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med. 1996;2:467–9.Google Scholar
  106. 106.
    Barton-Davis ER, Cordier L, Shoturma DI, Leland SE, Sweeney HL. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest. 1999;104:375–81.Google Scholar
  107. 107.
    Wilschanski M, Famini C, Blau H, Rivlin J, Augarten A, Avital A, Kerem B, Kerem E. A pilot study of the effect of gentamicin on nasal potential difference measurements in cystic fibrosis patients carrying stop mutations. Am J Respir Crit Care Med. 2000;161:860–5.Google Scholar
  108. 108.
    Clancy JP, Bebök Z, Ruiz F, King C, Jones J, Walker L, Greer H, Hong J, Wing L, Macaluso M, Lyrene R, Sorscher EJ, Bedwell DM. Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am J Respir Crit Care Med. 2001;163:1683–92.Google Scholar
  109. 109.
    Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, Aviram M, Bdolah-Abram T, Bebok Z, Shushi L, Kerem B, Kerem E. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N Engl J Med. 2003;349:1433–41.Google Scholar
  110. 110.
    Linde L, Boelz S, Nissim-Rafinia M, Oren YS, Wilschanski M, Yaacov Y, Virgilis D, Neu-Yilik G, Kulozik AE, Kerem E, Kerem B. Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. J Clin Invest. 2007;117:683–92.Google Scholar
  111. 111.
    Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D, Cohen M, Nissim-Rafinia M, Blau H, Rivlin J, Aviram M, Elfring GL, Northcutt VJ, Miller LL, Kerem B, Wilschanski M. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet. 2008;372:719–27.Google Scholar
  112. 112.
    Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, Roussel D, Fritsch J, Hanssens L, Hirawat S, Miller NL, Constantine S, Reha A, Ajayi T, Elfring GL, Miller LL. Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. Am J Respir Crit Care Med. 2010;182:1262–72.Google Scholar
  113. 113.
    Wilschanski M, Miller LL, Shoseyov D, Blau H, Rivlin J, Aviram M, Cohen M, Armoni S, Yaakov Y, Pugatsch T, Cohen-Cymberknoh M, Miller NL, Reha A, Northcutt VJ, Hirawat S, Donnelly K, Elfring GL, Ajayi T, Kerem E. Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. Eur Respir J. 2011;38:59–69.Google Scholar
  114. 114.
    Kerem E, Konstan MW, De Boeck K, Accurso FJ, Sermet-Gaudelus I, Wilschanski M, Elborn JS, Melotti P, Bronsveld I, Fajac I, Malfroot A, Rosenbluth DB, Walker PA, McColley SA, Knoop C, Quattrucci S, Rietschel E, Zeitlin PL, Barth J, Elfring GL, Welch EM, Branstrom A, Spiegel RJ, Peltz SW, Ajayi T. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med. 2014;2:539–47.Google Scholar
  115. 115.
    Zainal Abidin N, Haq IJ, Gardner AI, Brodlie M. Ataluren in cystic fibrosis: development, clinical studies and where are we now? Expert Opin Pharmacother. 2017;18:1363–71.Google Scholar
  116. 116.
    Altamura N, Castaldo R, Finotti A, Breveglieri G, Salvatori F, Zuccato C, Gambari R, Panin GC, Borgatti M. Tobramycin is a suppressor of premature termination codons. J Cyst Fibros. 2013;12:806–11.Google Scholar
  117. 117.
    Altamura E, Borgatti M, Finotti A, Gasparello J, Gambari R, Spinelli M, Castaldo R, Altamura N. Chemical-induced read-through at premature termination codons determined by a rapid dual-fluorescence system based on S. cerevisiae. PLoS ONE. 2016;11:e0154260.Google Scholar
  118. 118.
    Benhabiles H, Gonzalez-Hilarion S, Amand S, Bailly C, Prévotat A, Reix P, Hubert D, Adriaenssens E, Rebuffat S, Tulasne D, Lejeune F. Optimized approach for the identification of highly efficient correctors of nonsense mutations in human diseases. PLoS ONE. 2017;12:e0187930.Google Scholar
  119. 119.
    Pranke I, Bidou L, Martin N, Blanchet S, Hatton A, Karri S, Cornu D, Costes B, Chevalier B, Tondelier D, Girodon E, Coupet M, Edelman A, Fanen P, Namy O, Sermet-Gaudelus I, Hinzpeter A. Factors influencing readthrough therapy for frequent cystic fibrosis premature termination codons. ERJ Open Res. 2018;4:00080–2017.Google Scholar
  120. 120.
    Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, Wang LT, Ingenito EP, McKee C, Lu Y, Lekstrom-Himes J, Elborn JS. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377:2013–23.Google Scholar
  121. 121.
    Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, Nair N, Simard C, Han L, Ingenito EP, McKee C, Lekstrom-Himes J, Davies JC. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377:2024–35.Google Scholar
  122. 122.
    Donaldson SH, Pilewski JM, Griese M, Cooke J. Tezacaftor/ivacaftor in subjects with cystic fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. Am J Respir Crit Care Med. 2018;197:214–24.Google Scholar
  123. 123.
    Davies JC, Moskowitz SM, Brown C, Horsley A, Mall MA, McKone EF, Plant BJ, Prais D, Ramsey BW, Taylor-Cousar JL, Tullis E, Uluer A, McKee CM, Robertson S, Shilling RA, Simard C. VX-659 tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med. 2018;379:1599–611.Google Scholar
  124. 124.
    Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Sass LA, Tullis E, McKee CM, Moskowitz SM, Robertson S, Savage J, Simard C. VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med. 2018;379:1612–20.Google Scholar
  125. 125.
    Liessi N, Cichero E, Pesce E, Arkel M, Salis A, Tomati V, Paccagnella M, Damonte G, Tasso B, Galietta LJV, Pedemonte N, Fossa P, Millo E. Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools. Eur J Med Chem. 2018;144:179–200.Google Scholar
  126. 126.
    Wang X, Liu B, Searle X, Yeung C, Bogdan A, Greszler S, Singh A, Fan Y, Swensen AM, Vortherms T, Balut C, Jia Y, Desino K, Gao W, Yong H, Tse C, Kym P. Discovery of 4-[(2R,4R)-4-({[1-(2,2-Difluoro-1,3-benzodioxol-5cyclopropyl]carbonyl}amino) 7(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic Acid (ABBV/GLPG-2222), a potent cystic fibrosis transmembrane conductance regulator (CFTR) corrector for the treatment of cystic fibrosis. J Med Chem. 2018;61:1436–49.Google Scholar
  127. 127.
    Pesci E, Bettinetti L, Fanti P, Galietta LJ, La Rosa S, Magnoni L, Pedemonte N, Sardone GL, Maccari L. Novel hits in the correction of ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR) protein: synthesis, pharmacological, and ADME evaluation of tetrahydropyrido[4,3-d]pyrimidines for the potential treatment of cystic fibrosis. J Med Chem. 2015;58:9697–711.Google Scholar
  128. 128.
    Cendret V, Legigan T, Mingot A, Thibaudeau S, Adachi I, Forcella M, Parenti P, Bertrand J, Becq F, Norez C, Désiré J, Kato A, Blériot Y. Synthetic deoxynojirimycin derivatives bearing a thiolated, fluorinated or unsaturated N-alkyl chain: identification of potent α-glucosidase and trehalase inhibitors as well as F508del-CFTR correctors. Org Biomol Chem. 2015;13(43):10734–44.Google Scholar
  129. 129.
    Pesce E, Bellotti M, Liessi N, Guariento S, Damonte G, Cichero E, Galatini A, Salis A, Gianotti A, Pedemonte N, Zegarra-Moran O, Fossa P, Galietta LJ, Millo E. Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis. Eur J Med Chem. 2015;99:14–35.Google Scholar
  130. 130.
    Ye L, Hu B, El-Badri F, Hudson BM, Phuan PW, Verkman AS, Tantillo DJ, Kurth MJ. ΔF508-CFTR correctors: synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles. Bioorg Med Chem Lett. 2014;24:5840–4.Google Scholar
  131. 131.
    Coffman KC, Nguyen HH, Phuan PW, Hudson BM, Yu GJ, Bagdasarian AL, Montgomery D, Lodewyk MW, Yang B, Yoo CL, Verkman AS, Tantillo DJ, Kurth MJ. Constrained bithiazoles: small molecule correctors of defective ΔF508-CFTR protein trafficking. J Med Chem. 2014;57:6729–38.Google Scholar
  132. 132.
    Favia M, Mancini MT, Bezzerri V, Guerra L, Laselva O, Abbattiscianni AC, Debellis L, Reshkin SJ, Gambari R, Cabrini G, Casavola V. Trimethylangelicin promotes the functional rescue of mutant F508del CFTR protein in cystic fibrosis airway cells. Am J Physiol Lung Cell Mol Physiol. 2014;307:L48–61.Google Scholar
  133. 133.
    Phuan PW, Veit G, Tan J, Roldan A, Finkbeiner WE, Lukacs GL, Verkman AS. Synergy-based small-molecule screen using a human lung epithelial cell line yields ΔF508-CFTR correctors that augment VX-809 maximal efficacy. Mol Pharmacol. 2014;86:42–51.Google Scholar
  134. 134.
    Compain P, Decroocq C, Joosten A, de Sousa J, Rodríguez-Lucena D, Butters TD, Bertrand J, Clément R, Boinot C, Becq F, Norez C. Rescue of functional CFTR channels in cystic fibrosis: a dramatic multivalent effect using iminosugar cluster-based correctors. ChemBioChem. 2013;14:2050–8.Google Scholar
  135. 135.
    Odolczyk N, Fritsch J, Norez C, Servel N, da Cunha MF, Bitam S, Kupniewska A, Wiszniewski L, Colas J, Tarnowski K, Tondelier D, Roldan A, Saussereau EL, Melin-Heschel P, Wieczorek G, Lukacs GL, Dadlez M, Faure G, Herrmann H, Ollero M, Becq F, Zielenkiewicz P, Edelman A. Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain. EMBO Mol Med. 2013;5:1484–501.Google Scholar
  136. 136.
    Phuan PW, Yang B, Knapp JM, Wood AB, Lukacs GL, Kurth MJ, Verkman AS. Cyanoquinolines with independent corrector and potentiator activities restore ΔPhe508-cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis. Mol Pharmacol. 2011;80:683–93.Google Scholar
  137. 137.
    Pedemonte N, Tomati V, Sondo E, Caci E, Millo E, Armirotti A, Damonte G, Zegarra-Moran O, Galietta LJ. Dual activity of aminoarylthiazoles on the trafficking and gating defects of the cystic fibrosis transmembrane conductance regulator chloride channel caused by cystic fibrosis mutations. J Biol Chem. 2011;286:15215–26.Google Scholar
  138. 138.
    Kalid O, Mense M, Fischman S, Shitrit A, Bihler H, Ben-Zeev E, Schutz N, Pedemonte N, Thomas PJ, Bridges RJ, Wetmore DR, Marantz Y, Senderowitz H. Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening. J Comput Aided Mol Des. 2010;24:971–91.Google Scholar
  139. 139.
    Kim Chiaw P, Wellhauser L, Huan LJ, Ramjeesingh M, Bear CE. A chemical corrector modifies the channel function of F508del-CFTR. Mol Pharmacol. 2010;78:411–8.Google Scholar
  140. 140.
    Ye L, Knapp JM, Sangwung P, Fettinger JC, Verkman AS, Kurth MJ. Pyrazolylthiazole as DeltaF508-cystic fibrosis transmembrane conductance regulator correctors with improved hydrophilicity compared to bithiazoles. J Med Chem. 2010;53:3772–81.Google Scholar
  141. 141.
    Yu GJ, Yang B, Verkman AS, Kurth MJ. Isoxazolopyrimidines as novel ΔF508-CFTR correctors. Synlett. 2010;2010:1063–6.Google Scholar
  142. 142.
    Wellhauser L, Kim Chiaw P, Pasyk S, Li C, Ramjeesingh M, Bear CE. A small-molecule modulator interacts directly with deltaPhe508-CFTR to modify its ATPase activity and conformational stability. Mol Pharmacol. 2009;75:1430–8.Google Scholar
  143. 143.
    Yu GJ, Yoo CL, Yang B, Lodewyk MW, Meng L, El-Idreesy TT, Fettinger JC, Tantillo DJ, Verkman AS, Kurth MJ. Potent s-cis-locked bithiazole correctors of DeltaF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy. J Med Chem. 2008;51:6044–54.Google Scholar
  144. 144.
    Yoo CL, Yu GJ, Yang B, Robins LI, Verkman AS, Kurth MJ. 4’-Methyl-4,5’-bithiazole-based correctors of defective delta F508-CFTR cellular processing. Bioorg Med Chem Lett. 2008;18:2610–4.Google Scholar
  145. 145.
    Suen YF, Robins L, Yang B, Verkman AS, Nantz MH, Kurth MJ. Sulfamoyl-4-oxoquinoline-3-carboxamides: novel potentiators of defective DeltaF508-cystic fibrosis transmembrane conductance regulator chloride channel gating. Bioorg Med Chem Lett. 2006;16:537–40.Google Scholar
  146. 146.
    Pedemonte N, Diena T, Caci E, Nieddu E, Mazzei M, Ravazzolo R, Zegarra-Moran O, Galietta LJ. Antihypertensive 1,4-dihydropyridines as correctors of the cystic fibrosis transmembrane conductance regulator channel gating defect caused by cystic fibrosis mutations. Mol Pharmacol. 2005;68:1736–46.Google Scholar
  147. 147.
    Pedemonte N, Lukacs GL, Du K, Caci E, Zegarra-Moran O, Galietta LJ, Verkman AS. Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. J Clin Invest. 2005;115:2564–71.Google Scholar
  148. 148.
    Pedemonte N, Sonawane ND, Taddei A, Hu J, Zegarra-Moran O, Suen YF, Robins LI, Dicus CW, Willenbring D, Nantz MH, Kurth MJ, Galietta LJ, Verkman AS. Phenylglycine and sulfonamide correctors of defective delta F508 and G551D cystic fibrosis transmembrane conductance regulator chloride-channel gating. Mol Pharmacol. 2005;67:1797–807.Google Scholar
  149. 149.
    Yang H, Shelat AA, Guy RK, Gopinath VS, Ma T, Du K, Lukacs GL, Taddei A, Folli C, Pedemonte N, Galietta LJ, Verkman AS. Nanomolar affinity small molecule correctors of defective Delta F508-CFTR chloride channel gating. J Biol Chem. 2003;278:35079–85.Google Scholar
  150. 150.
  151. 151.
    Phuan PW, Veit G, Tan JA, Finkbeiner WE, Lukacs GL, Verkman AS. Potentiators of defective ΔF508-CFTR gating that do not interfere with corrector action. Mol Pharmacol. 2015;88:791–9.Google Scholar
  152. 152.
    Kerem E, Corey M, Kerem BS, Rommens J, Markiewicz D, Levison H, Tsui LC, Durie P. The relation between genotype and phenotype in cystic fibrosis–analysis of the most common mutation (delta F508). N Engl J Med. 1990;323:1517–22.Google Scholar
  153. 153.
    Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. N Engl J Med. 1993;329:1308–13.Google Scholar
  154. 154.
    Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, Rubenstein RC, Higgins M, VX11-770-110 (KONDUCT) Study Group. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet. Respir Med. 2015;3:524–33.Google Scholar
  155. 155.
    Kerem E, Kerem B. The relationship between genotype and phenotype in cystic fibrosis. Curr Opin Pulm Med. 1995;1:450–6.Google Scholar
  156. 156.
    Pagani F, Stuani C, Tzetis M, Kanavakis E, Efthymiadou A, Doudounakis S, Casals T, Baralle FE. New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12. Hum Mol Genet. 2003;12:1111–20.Google Scholar
  157. 157.
    Goina E, Fernandez-Alanis E, Pagani F. Approaches to study CFTR pre-mRNA splicing defects. Methods Mol Biol. 2011;741:155–69.Google Scholar
  158. 158.
    Dujardin G, Commandeur D, Le Jossic-Corcos C, Ferec C, Corcos L. Splicing defects in the CFTR gene: minigene analysis of two mutations, 1811 + 1G > C and 1898 + 3A > G. J Cyst Fibros. 2011;10:212–6.Google Scholar
  159. 159.
    Fernandez Alanis E, Pinotti M, Dal Mas A, Balestra D, Cavallari N, Rogalska ME, Bernardi F, Pagani F. An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Hum Mol Genet. 2012;21:2389–98.Google Scholar
  160. 160.
    Sharma M, Benharouga M, Hu W, Lukacs GL. Conformational and temperature-sensitive stability defects of the delta F508 cystic fibrosis transmembrane conductance regulator in post-endoplasmic reticulum compartments. J Biol Chem. 2001;276:8942–50.Google Scholar
  161. 161.
    Okiyoneda T, Barrière H, Bagdány M, Rabeh WM, Du K, Höhfeld J, Young JC, Lukacs GL. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science. 2010;329:805–10.Google Scholar
  162. 162.
    Fu L, Rab A, Lp Tang. Bebok Z, Rowe SM, Bartoszewski R, Collawn JF. ΔF508 CFTR surface stability is regulated by DAB2 and CHIP-mediated ubiquitination in post-endocytic compartments. PLoS ONE. 2015;10:e0123131.Google Scholar
  163. 163.
    Meng X, Clews J, Kargas V, Wang X, Ford RC. The cystic fibrosis transmembrane conductance regulator (CFTR) and its stability. Cell Mol Life Sci. 2017;74:23–38.Google Scholar
  164. 164.
    Guerra L, Fanelli T, Favia M, Riccardi SM, Busco G, Cardone RA, Carrabino S, Weinman EJ, Reshkin SJ, Conese M, Casavola V. Na +/H + exchanger regulatory factor isoform 1 overexpression modulates cystic fibrosis transmembrane conductance regulator (CFTR) expression and activity in human airway 16HBE14o- cells and rescues DeltaF508 CFTR functional expression in cystic fibrosis cells. J Biol Chem. 2005;280:40925–33.Google Scholar
  165. 165.
    Favia M, Guerra L, Fanelli T, Cardone RA, Monterisi S, Di Sole F, Castellani S, Chen M, Seidler U, Reshkin SJ, Conese M, Casavola V. Na +/H + exchanger regulatory factor 1 overexpression-dependent increase of cytoskeleton organization is fundamental in the rescue of F508del cystic fibrosis transmembrane conductance regulator in human airway CFBE41o- cells. Mol Biol Cell. 2010;21(1):73–86.Google Scholar
  166. 166.
    Rubino R, Bezzerri V, Favia M, Facchini M, Tebon M, Singh AK, Riederer B, Seidler U, Iannucci A, Bragonzi A, Cabrini G, Reshkin SJ, Tamanini A. Pseudomonas aeruginosa reduces the expression of CFTR via post-translational modification of NHERF1. Pflugers Arch. 2014;466:2269–78.Google Scholar
  167. 167.
    Rowe SM, Verkman AS. Cystic fibrosis transmembrane regulator correctors and potentiators. Cold Spring Harb Perspect Med. 2013;3:a009761.Google Scholar
  168. 168.
    Collawn JF, Fu L, Bartoszewski R, Matalon S. Rescuing ΔF508 CFTR with trimethylangelicin, a dual-acting corrector and potentiator. Am J Physiol Lung Cell Mol Physiol. 2014;307:L431–4.Google Scholar
  169. 169.
    Mills AD, Yoo C, Butler JD, Yang B, Verkman AS, Kurth MJ. Design and synthesis of a hybrid potentiator-corrector agonist of the cystic fibrosis mutant protein DeltaF508-CFTR. Bioorg Med Chem Lett. 2010;20:87–91.Google Scholar
  170. 170.
    Knapp JM, Wood AB, Phuan PW, Lodewyk MW, Tantillo DJ, Verkman AS, Kurth MJ. Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in ΔF508 cystic fibrosis transmembrane conductance regulator protein. J Med Chem. 2012;55:1242–51.Google Scholar
  171. 171.
    Tamanini A, Borgatti M, Finotti A, Piccagli L, Bezzerri V, Favia M, Guerra L, Lampronti I, Bianchi N, Dall’Acqua F, Vedaldi D, Salvador A, Fabbri E, Mancini I, Nicolis E, Casavola V, Cabrini G, Gambari R. Trimethylangelicin reduces IL-8 transcription and potentiates CFTR function. Am J Physiol Lung Cell Mol Physiol. 2011;300:L380–90.Google Scholar
  172. 172.
    Liu J, Bihler H, Farinha CM, Awatade NT, Romão AM, Mercadante D, Cheng Y, Musisi I, Jantarajit W, Wang Y, Cai Z, Amaral MD, Mense M, Sheppard DN. Partial rescue of F508del-CFTR channel gating with modest improvement of protein processing, but not stability by a dual-acting small molecule. Br J Pharmacol. 2018;175:1017–38.Google Scholar
  173. 173.
    Mendoza JL, Schmidt A, Li Q, Nuvaga E, Barrett T, Bridges RJ, Feranchak AP, Brautigam CA, Thomas PJ. Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences. Cell. 2012;148:164–74.Google Scholar
  174. 174.
    Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, Roldan A, Verkman AS, Kurth M, Simon A, Hegedus T, Beekman JM, Lukacs GL. Mechanism-based corrector combination restores ΔF508-CFTR folding and function. Nat Chem Biol. 2013;9:444–54.Google Scholar
  175. 175.
    He L, Kota P, Aleksandrov AA, Cui L, Jensen T, Dokholyan NV, Riordan JR. Correctors of ΔF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein. FASEB J. 2013;27:536–45.Google Scholar
  176. 176.
    Laselva O, Molinski S, Casavola V, Bear CE. The investigational cystic fibrosis drug trimethylangelicin directly modulates CFTR by stabilizing the first membrane-spanning domain. Biochem Pharmacol. 2016;119:85–92.Google Scholar
  177. 177.
    Balch WE, Roth DM, Hutt DM. Emergent properties of proteostasis in managing cystic fibrosis. Cold Spring Harb Perspect Biol. 2011;3:a004499.Google Scholar
  178. 178.
    Coppinger JA, Hutt DM, Razvi A, Koulov AV, Pankow S, Yates JR 3rd, Balch WE. A chaperone trap contributes to the onset of cystic fibrosis. PLoS ONE. 2012;7:e37682.Google Scholar
  179. 179.
    Lukacs GL, Verkman AS. CFTR: folding, misfolding and correcting the ΔF508 conformational defect. Trends Mol Med. 2012;18:81–91.Google Scholar
  180. 180.
    Norez C, Vandebrouck C, Bertrand J, Noel S, Durieu E, Oumata N, Galons H, Antigny F, Chatelier A, Bois P, Meijer L, Becq F. Roscovitine is a proteostasis regulator that corrects the trafficking defect of F508del-CFTR by a CDK-independent mechanism. Br J Pharmacol. 2014;171:4831–49.Google Scholar
  181. 181.
    Hegde RN, Parashuraman S, Iorio F, Ciciriello F, Capuani F, Carissimo A, Carrella D, Belcastro V, Subramanian A, Bounti L, Persico M, Carlile G, Galietta L, Thomas DY, Di Bernardo D, Luini A. Unravelling druggable signalling networks that control F508del-CFTR proteostasis. Elife 2015;4: e10365.Google Scholar
  182. 182.
    Ernst WL, Shome K, Wu CC, Gong X, Frizzell RA, Aridor M. VAMP-associated proteins (VAP) as receptors that couple cystic fibrosis transmembrane conductance regulator (CFTR) proteostasis with lipid homeostasis. J Biol Chem. 2016;291:5206–20.Google Scholar
  183. 183.
    Lopes-Pacheco M, Sabirzhanova I, Rapino D, Morales MM, Guggino WB, Cebotaru L. Correctors rescue CFTR mutations in nucleotide-binding domain 1 (NBD1) by modulating proteostasis. ChemBioChem. 2016;17:493–505.Google Scholar
  184. 184.
    Ramachandran S, Osterhaus SR, Parekh KR, Jacobi AM, Behlke MA, McCray PB Jr. SYVN1, NEDD8, and FBXO2 proteins regulate ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) ubiquitin-mediated proteasomal degradation. J Biol Chem. 2016;291:25489–504.Google Scholar
  185. 185.
    Adnan H, Zhang Z, Park HJ, Tailor C, Che C, Kamani M, Spitalny G, Binnington B, Lingwood C. Endoplasmic reticulum-targeted subunit toxins provide a new approach to rescue misfolded mutant proteins and revert cell models of genetic diseases. PLoS ONE. 2016;11:e0166948.Google Scholar
  186. 186.
    Lopes-Pacheco M, Boinot C, Sabirzhanova I, Rapino D, Cebotaru L. Combination of correctors rescues CFTR transmembrane-domain mutants by mitigating their interactions with proteostasis. Cell Physiol Biochem. 2017;41:2194–210.Google Scholar
  187. 187.
    Rubenstein RC, Egan ME, Zeitlin PL. In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR. J Clin Invest. 1997;100:2457–65.Google Scholar
  188. 188.
    Rubenstein RC, Zeitlin PL. A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in deltaF508-homozygous cystic fibrosis patients: partial restoration of nasal epithelial CFTR function. Am J Respir Crit Care Med. 1998;157:484–90.Google Scholar
  189. 189.
    Chung WJ, Goeckeler-Fried JL, Havasi V, Chiang A, Rowe SM, Plyler ZE, Hong JS, Mazur M, Piazza GA, Keeton AB, White EL, Rasmussen L, Weissman AM, Denny RA, Brodsky JL, Sorscher EJ. Increasing the endoplasmic reticulum pool of the F508del allele of the cystic fibrosis transmembrane conductance regulator leads to greater folding correction by small molecule therapeutics. PLoS ONE. 2016;11:e0163615.Google Scholar
  190. 190.
    Giuliano KA, Wachi S, Drew L, Dukovski D, Green O, Bastos C, Cullen MD, Hauck S, Tait BD, Munoz B, Lee PS, Miller JP. 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;23:111–21.Google Scholar
  191. 191.
    Molinski SV, Ahmadi S, Ip W, Ouyang H, Villella A, Miller JP, Lee PS, Kulleperuma K, Du K, Di Paola M, Eckford PD, Laselva O, Huan LJ, Wellhauser L, Li E, Ray PN, Pomès R, Moraes TJ, Gonska T, Ratjen F, Bear CE. Orkambi® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue. EMBO Mol Med. 2017;9:1224–43.Google Scholar
  192. 192.
    Fabbri E, Tamanini A, Jakova T, Gasparello J, Manicardi A, Corradini R, Sabbioni G, Finotti A, Borgatti M, Lampronti I, Munari S, Dechecchi MC. A peptide nucleic acid against microRNA miR-145-5p enhances the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in Calu-3 cells. Molecules. 2017;pii:E71.Google Scholar
  193. 193.
    Crystal RG, McElvaney NG, Rosenfeld MA, Chu CS, Mastrangeli A, Hay JG, Brody SL, Jaffe HA, Eissa NT, Danel C. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet. 1994;8:42–51.Google Scholar
  194. 194.
    Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, Wilson JM, Batshaw ML. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80:148–58.Google Scholar
  195. 195.
    Davies JC, Alton EW. Airway gene therapy. Adv Genet. 2005;54:291–314.Google Scholar
  196. 196.
    Gruenert DC, Bruscia E, Novelli G, Colosimo A, Dallapiccola B, Sangiuolo F, Goncz KK. Sequence-specific modification of genomic DNA by small DNA fragments. J Clin Invest. 2003;112:637–41.Google Scholar
  197. 197.
    Harrison PT, Sanz DJ, Hollywood JA. Impact of gene editing on the study of cystic fibrosis. Hum Genet. 2016;135:983–92.Google Scholar
  198. 198.
    Cholon DM, Gentzsch M. Recent progress in translational cystic fibrosis research using precision medicine strategies. J Cyst Fibros. 2018;17:S52–60.Google Scholar
  199. 199.
    Roesch EA, Drumm ML. Powerful tools for genetic modification: advances in gene editing. Pediatr Pulmonol. 2017;52:S15–20.Google Scholar
  200. 200.
    Vallecillo-Viejo IC, Liscovitch-Brauer N, Montiel-Gonzalez MF, Eisenberg E, Rosenthal JJC. Abundant off-target edits from site-directed RNA editing can be reduced by nuclear localization of the editing enzyme. RNA Biol. 2018;15:104–14.Google Scholar
  201. 201.
    Hollywood JA, Lee CM, Scallan MF, Harrison PT. Analysis of gene repair tracts from Cas9/gRNA double-stranded breaks in the human CFTR gene. Sci Rep. 2016;6:32230.Google Scholar
  202. 202.
    Lee CM, Flynn R, Hollywood JA, Scallan MF, Harrison PT. Correction of the ΔF508 Mutation in the cystic fibrosis transmembrane conductance regulator gene by zinc-finger nuclease homology-directed repair. Biores Open Access. 2012;1:99–108.Google Scholar
  203. 203.
    Sanz DJ, Hollywood JA, Scallan MF, Harrison PT. Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA. PLoS ONE. 2017;12:e0184009.Google Scholar
  204. 204.
    Casini A, Olivieri M, Petris G, Montagna C, Reginato G, Maule G, Lorenzin F, Prandi D, Romanel A, Demichelis F, Inga A, Cereseto A. A highly specific SpCas9 variant is identified by in vivo screening in yeast. Nat Biotechnol. 2018;36:265–71.Google Scholar
  205. 205.
    Veit G, Bossard F, Goepp J, Verkman AS, Galietta LJ, Hanrahan JW, Lukacs GL. Proinflammatory cytokine secretion is suppressed by TMEM16A or CFTR channel activity in human cystic fibrosis bronchial epithelia. Mol Biol Cell. 2012;23:4188–202.Google Scholar
  206. 206.
    Ruffin M, Roussel L, Maillé É, Rousseau S, Brochiero E. Vx-809/Vx-770 treatment reduces inflammatory response to Pseudomonas aeruginosa in primary differentiated cystic fibrosis bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2018;314:L635–41.Google Scholar
  207. 207.
    Barnaby R, Koeppen K, Nymon A, Hampton TH, Berwin B, Ashare A, Stanton B. Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol. 2018;314:L432–8.Google Scholar
  208. 208.
    Dechecchi MC, Nicolis E, Norez C, Bezzerri V, Borgatti M, Mancini I, Rizzotti P, Ribeiro CM, Gambari R, Becq F, Cabrini G. Anti-inflammatory effect of miglustat in bronchial epithelial cells. J Cyst Fibros. 2008;7:555–65.Google Scholar
  209. 209.
    Lampronti I, Manzione MG, Sacchetti G, Ferrari D, Spisani S, Bezzerri V, Finotti A, Borgatti M, Dechecchi MC, Miolo G, Marzaro G, Cabrini G, Gambari R, Chilin A. Differential effects of angelicin analogues on NF-κB activity and IL-8 gene expression in cystic fibrosis IB3-1 cells. Med Inflamm. 2017;2017:2389487.Google Scholar
  210. 210.
    Döring G, Flume P. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J Cyst Fibros. 2012;11:461–79.Google Scholar
  211. 211.
    Nichols DP, Chmiel JF. Inflammation and its genesis in cystic fibrosis. Pediatr Pulmonol. 2015;50:S39–56.Google Scholar
  212. 212.
    Torphy TJ, Allen J, Cantin AM, Konstan MW, Accurso FJ. Considerations for the conduct of clinical trials with antiinflammatory agents in cystic fibrosis. A cystic fibrosis foundation workshop report. Ann Am Thorac Soc. 2015;12:1398–406.Google Scholar
  213. 213.
    Cantin AM, Hartl D, Konstan MW, Chmiel JF. Inflammation in cystic fibrosis lung disease: pathogenesis and therapy. J Cyst Fibros. 2015;14:419–30.Google Scholar
  214. 214.
    Roesch EA, Nichols DP, Chmiel JF. Inflammation in cystic fibrosis: an update. Pediatr Pulmonol. 2018;53:S30–50.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Laboratory of Molecular PathologyUniversity HospitalVeronaItaly
  2. 2.Department of Neurosciences, Biomedicine and Movement SciencesUniversity of VeronaVeronaItaly

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