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

European Journal of Pediatrics

Volumn 175, Issue 1, 2016, Pages 1-8

  Bosch, Barbara ^a   De Boeck, Kris ^a  

^a UNIVERSITY HOSPITALS LEUVEN   (Belgium)

Author keywords

CFTR; Clinical trials; Corrector; Cystic fibrosis; N of 1 trial; Organoids; Potentiator

Indexed keywords

CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; IVACAFTOR PLUS LUMACAFTOR; MESSENGER RNA; CFTR PROTEIN, HUMAN;

CELL MEMBRANE; CLINICAL TRIAL (TOPIC); CYSTIC FIBROSIS; GENE MUTATION; GENE THERAPY; HUMAN; PRIORITY JOURNAL; PROTEIN FOLDING; PROTEIN TRANSPORT; REVIEW; RNA TRANSLATION; TREATMENT RESPONSE; GENETICS; PHYSIOLOGY; PROTEIN SYNTHESIS;

CYSTIC FIBROSIS; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; GENETIC THERAPY; HUMANS; PROTEIN BIOSYNTHESIS; RNA, MESSENGER;

EID: 84954386815     PISSN: 03406199     EISSN: 14321076     Source Type: Journal    
DOI: 10.1007/s00431-015-2664-8     Document Type: Review

References (46)

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
2. Aurino S, Nigro V (2006) Readthrough strategies for stop codons in Duchenne muscular dystrophy. Acta Myol 25(1):5–12
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
4. Bell SC, De Boeck K, Amaral MD (2015) New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Pharmacol Ther 145:19–34
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
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
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
9. Castellani S, Conese M (2010) Lentiviral vectors and cystic fibrosis gene therapy. Viruses 2(2):395–412
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
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
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
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
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
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
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
19. Derichs N (2013) Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Eur Respir Rev 22(127):58–65
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
21. Griesenbach U, Alton E (2013) Moving forward: cystic fibrosis gene therapy. Hum Mol Genet 22(R1):R52–58
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
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
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
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
26. 1 decline in cystic fibrosis: analysis of the ECFS Patient Registry. Eur Respir J 43:125–133
27. Kleizen B, van Vlijmen T, de Jonghe H, Braakman I (2005) Folding of CFTR is predominantly cotranslational. Mol Cell 20(2):277–287
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
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
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
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
32. Porensky PN, Burghes AHM (2013) Antisense oligonucleotides for the treatment of spinal muscular atrophy. Hum Gene Ther 24(5):489–498
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
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
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
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
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
38. Rowe SM, Miller S, Sorcher E (2005) Cystic fibrosis. N Engl J Med 352:1992–2001
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
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
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
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
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