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Searching for a cure for cystic fibrosis. A 25-year quest in a nutshell

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Abstract

After 25 years of intensive search, there is not yet a cure for cystic fibrosis (CF). However, the quest has led to major breakthroughs in understanding the basic disease defect and defining strategies to correct it. The first cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been introduced in clinic. Some show an impressive clinical benefit, like the potentiator ivacaftor for the 4 % of patients with a class III defect. Others offer at present only a limited benefit, like the combination corrector lumacaftor plus potentiator ivacaftor for subjects homozygous for F508del. These findings prove that the basic defect in CF can be modified and hold the promise that one day CF will no longer be a life-shortening disease.

Conclusion: This review updates the clinician on recent achievements as well as on the CF research pipeline.

What is Known:

• Cystic fibrosis (CF) is a common and life-shortening disease that currently cannot be cured.

• However, for each of the six CF mutation classes, disease-modifying drugs are under way.

What is New:

• This review is a concise update for the clinician on new drugs that reached the CF clinical pipeline.

• The research strategies in CF have become a paradigm for clinical trials in other inherited diseases.

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Abbreviations

CF:

Cystic Fibrosis

CFTR:

Cystic Fibrosis Transmembrane Conductance Regulator

FEV1 :

Forced Expiratory Volume in 1 s

NCT:

National Clinical Trial

PTC:

Post-Transcriptional Control

References

  1. Alton EW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Bloomfield EV, Boyd AC, Brand J, Buchan R, Calcedo R, Carvelli P, Chan M, Cheng SH, Collie DD, Cunningham S, Davidson HE, Davies G, Davies JC, Davies LA, Dewar MH, Doherty A, Donovan J, Dwyer NS, Elgmati HI, Featherstone RF, Gavino J, Gea-Sorli S, Geddes DM, Gibson JS, Gill DR, Greening AP, Griesenbach U, Hansell DM, Harman K, Higgins TE, Hodges SL, Hyde SC, Hyndman L, Innes JA, Jacob J, Jones N, Keogh BF, Limberis MP, Lloyd-Evans P, Maclean AW, Manvell MC, McCormick D, McGovern M, McLachlan G, Meng C, Montero MA, Milligan H, Moyce LJ, Murray GD, Nicholson AG, Osadolor T, Parra-Leiton J, Porteous DJ, Pringle IA, Punch EK, Pytel KM, Quittner AL, Rivellini G, Saunders CJ, Scheule RK, Sheard S, Simmonds NJ, Smith K, Smith SN, Soussi N, Soussi S, Spearing EJ, Stevenson BJ, Sumner-Jones SG, Turkkila M, Ureta RP, Waller MD, Wasowicz MY, Wilson JM, Wolstenholme-Hogg P, UK Cystic Fibrosis Gene Therapy Consortium (2015) 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. doi:10.1016/S2213-2600(15)00245-3

    PubMed  PubMed Central  Google Scholar 

  2. Aurino S, Nigro V (2006) Readthrough strategies for stop codons in Duchenne muscular dystrophy. Acta Myol 25(1):5–12

    PubMed  CAS  Google Scholar 

  3. Awatade NT, Uliyakina I, Farinha CM, Clarke LA, Mendes K, Solé A, Pastor J, Ramos MM, Amaral MD (2014) Measurements of functional responses in human primary lung cells as a basis for personalized therapy for cystic fibrosis. EBioMedicine 2(2):147–53

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bell SC, De Boeck K, Amaral MD (2015) New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Pharmacol Ther 145:19–34

    Article  PubMed  CAS  Google Scholar 

  5. Borowitz D, Lubarsky B, Wilschanski M, Munck A, Gelfond D, Bodewes F, Schwarzenberg SJ (2015). Nutritional status improved in cystic fibrosis patients with the G551D mutation after treatment with ivacaftor. PMID: 26250833

  6. Boyle MP, De Boeck K (2013) A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med 1(2):101

    Article  Google Scholar 

  7. Bush A, Simmonds NJ (2012) Hot off the breath: ‘I’ve a cost for’—the 64 million dollar question. Thorax 67(5):382–4

    Article  PubMed  Google Scholar 

  8. Carlon MS, Vidovic D, Dekkers JF, Faria da Cunha M, Hollenhorst MI, Bijvelds M, Van den Haute C, Baekelandt V, de Jonge H, De Boeck K, Gijsbers R, Sermet-Gaudelus I, Edelman A, Beekman J, Debyser Z (2015) rAAV2/5 encoding a truncated CFTR rescues the CF phenotype in intestinal organoids and a CF mouse model. J Cyst Fibros 14(1):S1

    Article  Google Scholar 

  9. Castellani S, Conese M (2010) Lentiviral vectors and cystic fibrosis gene therapy. Viruses 2(2):395–412

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Castellani C, Kuppens H, Macek M, Cassiman JJ, Kerem E, Durie P, Tullis E, Assael BM, Bombieri C, Brown A, Casals T, Claustres M, Cutting GR, Dequeker E, Dodge J, Doull I, Farrell P, Ferec C, Girodon E, Johannesson M, Kerem B, Knowles M, Munck A, Pignatti PF, Radojkovic D, Rizzotti P, Schwarz M, Stuhrmann M, Tzetis M, Zielenski J, Elborn JS (2008) Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros 7(3):179–196

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Cftr.info (2015) Classification of CFTR mutations. Available via URL: http://www.cftr.info/about-cf/role-of-ctfr-in-cf/cftr-mutations/the-six-classes-of-cftr-defects/ Accessed 9 Sept 2015

  12. Cholon DM, Quinney NL, Fulcher ML, Esther CR Jr, Das J, Dokholyan NV, Randell SH, Boucher RC, Gentzsch M (2014) Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis. Sci Transl Med 6(246):246ra96

    Article  PubMed  PubMed Central  Google Scholar 

  13. 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 (2012) 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 67(1):12–8

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. De Boeck K, Fajac I, Ratjen F (2014) End-points and biomarkers for clinical trials in cystic fibrosis. In: Mall M, Elborn JS (eds) ERS Monograph Cystic Fibrosis. No. 64 (2014) 104–115

    Google Scholar 

  15. De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M (2014) Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros 3(6):674–80

    Article  Google Scholar 

  16. De Boeck K, Zolinb A, Cuppens H, Olesend HV, Vivianib L (2014) The relative frequency of CFTR mutation classes in European patients with cystic fibrosis. J Cyst Fibrosis 13(4):403–409

    Article  Google Scholar 

  17. De Boer D (2014) PROQR THERAPEUTICS N.V. (PRQR) IPO. Company Description. Available via URL: http://www.nasdaq.com/markets/ipos/company/proqr-therapeutics-nv-942327-76207 Accessed 9 Sept 2015

  18. 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 (2013) A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med 19:939–945

    Article  PubMed  CAS  Google Scholar 

  19. Derichs N (2013) Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Eur Respir Rev 22(127):58–65

    Article  PubMed  Google Scholar 

  20. De Stefano D, Villella VR, Esposito S, Tosco A, Sepe A, De Gregorio F, Salvadori L, Grassia R, Leone CA, De Rosa G, Maiuri MC, Pettoello-Mantovani M, Guido S, Bossi A, Zolin A, Venerando A, Pinna LA, Mehta A, Bona G, Kroemer G, Maiuri L, Raia V (2014) Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation. Autophagy 10(11):2053–74

    Article  PubMed  PubMed Central  Google Scholar 

  21. Griesenbach U, Alton E (2013) Moving forward: cystic fibrosis gene therapy. Hum Mol Genet 22(R1):R52–58

    Article  PubMed  CAS  Google Scholar 

  22. Halbert CL, Standaert TA, Aitken ML, Alexander IE, Russell DW, Miller AD (1997) Transduction by adeno-associated virus vectors in the rabbit airway: efficiency, persistence, and readministration. J Virol 71(8):5932–41

    PubMed  CAS  PubMed Central  Google Scholar 

  23. Irony Tur-Sinai M, Wilton S, Kerem B (2014) Restoration of the CFTR function by antisense oligonucleotide splicing modulation. J Cyst Fibros. doi:10.1016/S1569-1993(14)60008-4

    Google Scholar 

  24. Kent L, Reix P, Innes JA, Zielen S, Le Bourgeois M, Braggion C, Lever S, Arets HG, Brownlee K, Bradley JM, Bayfield K, O’Neill K, Savi D, Bilton D, Lindblad A, Davies JC, Sermet I, De Boeck K, European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) Standardisation Committee (2014) Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros 13(2):123–38

    Article  PubMed  Google Scholar 

  25. 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, Cystic RSM, Group FAS (2014) Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med 2(7):539–47

    Article  PubMed  CAS  Google Scholar 

  26. Kerem E, Viviani L, Zolin A, MacNeill S, Hatziagorou E, Ellemunter H, Drevinek P, Gulmans V, Krivec U, Olesen H, ECFS Patient Registry Steering Group (2014) Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS Patient Registry. Eur Respir J 43:125–133

    Article  PubMed  Google Scholar 

  27. Kleizen B, van Vlijmen T, de Jonghe H, Braakman I (2005) Folding of CFTR is predominantly cotranslational. Mol Cell 20(2):277–287

    Article  PubMed  CAS  Google Scholar 

  28. Lillie EO, Patay B, Diamant J, Issell B, Topol EJ, Schork NJ (2011) The n-of-1 clinical trial: the ultimate strategy for individualizing medicine? Per Med 8(2):161–173

    Article  PubMed  PubMed Central  Google Scholar 

  29. Montiel-Gonzalez MF, Vallecillo-Viejo I, Yudowski GA, Rosenthal JJC (2013) Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing. Proc Natl Acad Sci U S A 110(45):18285–18290

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, Rubenstein RC, Higgins M, VX11-770-110 (KONDUCT) Study Group (2015) 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 3(7):524–33

    Article  PubMed  CAS  Google Scholar 

  31. 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 (2013) Mechanism-based corrector combination restores ΔF508-CFTR folding and function. Nat Chem Biol 9(7):444–54

    Article  PubMed  CAS  Google Scholar 

  32. Porensky PN, Burghes AHM (2013) Antisense oligonucleotides for the treatment of spinal muscular atrophy. Hum Gene Ther 24(5):489–498

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Proesmans M, Vermeulen F, De Boeck K (2008) What’s new in cystic fibrosis? From treating symptoms to correction of the basic defect. Eur J Pediatr 167(8):839–49

    Article  PubMed  Google Scholar 

  34. Ramsey BW, Davies J, McElvany TE, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS, VX08-770-102 Study Group (2011) A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 365(18):1663–72

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Ren HY, Grove DE, De La Rosa O, Houck SA, Sopha P, Van Goor F, Hoffman BJ, Cyr DM (2013) VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell 24(19):3016–24

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N (1989) Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245(4922):1059–65

    Article  PubMed  CAS  Google Scholar 

  37. Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, Sagel SD, Khan U, Mayer-Hamblett N, Van Dalfsen JM, Joseloff E, Ramsey BW, GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network (2014) Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 190(2):175–84

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Rowe SM, Miller S, Sorcher E (2005) Cystic fibrosis. N Engl J Med 352:1992–2001

    Article  PubMed  CAS  Google Scholar 

  39. Sawicki GS, McKone EF, Pasta DJ, Millar SJ, Wagener JS, Johnson CA, Konstan MW (2015) Sustained benefit from ivacaftor demonstrated by combining clinical trial and CF patient registry data. Am J Respir Crit Care Med. [Epub ahead of print]

  40. 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 (2006) Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol Lung Cell Mol Physiol 290(6):L1117–30

    Article  PubMed  Google Scholar 

  41. Van Goor F, Yu H, Burton B, Hoffman BJ (2014) Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros 13(1):29–36

    Article  PubMed  Google Scholar 

  42. Vertex Pharmaceuticals Incorporated (2012) Study of VX-661 alone and in combination with ivacaftor in subjects homozygous or heterozygous to the F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation. ClinicalTrials.gov Identifier: NCT01531673. Available via URL: https://www.clinicaltrials.gov/ct2/show/NCT01531673?term=vertex&cond=%22Cystic+Fibrosis%22&rank=2 Last accessed 09 Sept 2015

  43. Vertex Pharmaceuticals Incorporated (2014). Addition of VX-661 to KALYDECO® (ivacaftor) Improves lung function in people with CF who are heterozygous for the F508del and G551D mutations in 28-day phase 2 proof-of-concept study. Available via URL: http://investors.vrtx.com/releasedetail.cfm?releaseid=844677. Last accessed 24 Oct 2015. 5). Vertex Announces Data from 12-Week Phase 2 Safety Study of VX-661 in Combination with Ivacaftor in People with Cystic Fibrosis Who Have Two Copies of the F508del Mutation. Available via URL http://investors.vrtx.com/releasedetail.cfm?ReleaseID=902790 Last accessed 09 Sept 2015

  44. Wainwright CE, Elborn S, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP, TRAFFIC and TRANSPORT Study Groups (2015) Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 373:220–231

    Article  PubMed  CAS  Google Scholar 

  45. Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL (2007) PTC124 targets genetic disorders caused by nonsense mutations. Nature 447(7140):87–91

    Article  PubMed  CAS  Google Scholar 

  46. Zamecnik PC, Raychowdhury MK, Tabatadze DR, Cantiello HF (2004) Reversal of cystic fibrosis phenotype in a cultured Δ508 cystic fibrosis transmembrane conductance regulator cell line by oligonucleotide insertion. Proc Natl Acad Sci U S A 101(21):8150–8155

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Authors’ contribution

Both authors contributed substantially to the manuscript.

BB drafted the work. KDB revised it critically.

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Authors and Affiliations

  1. Department of Paediatric Pulmonology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Barbara Bosch & Kris De Boeck

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  1. Barbara Bosch
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Correspondence to Barbara Bosch.

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Funding

B. Bosch is funded by the Flanders Research Foundation (FWO), grant number: 11V5316N.

Conflict of interest

Barbara Bosch has no conflict of interest. Kris De Boeck has been and is the principal investigator for the ivacaftor/lumacaftor clinical trials and has received payments for Vertex advisory board and Vertex satellite symposia participation.

She has also obtained fees for consultancy or participation in advisory boards from Aptalis, Bayer, Boehringer, Celtaxsys, Galapagos, Gilead, Pharmaxis, ProQR, PTC and Roche.

Ethical approval

All clinical trials described in this review were approved by the ethics committee

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Communicated by Peter de Winter

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Bosch, B., De Boeck, K. Searching for a cure for cystic fibrosis. A 25-year quest in a nutshell. Eur J Pediatr 175, 1–8 (2016). https://doi.org/10.1007/s00431-015-2664-8

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