title: Cystic Fibrosis Gene Therapy in the UK and Elsewhere.
abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here.
authors.affiliation: Department of Gene Therapy and the U.K. Cystic Fibrosis Gene Therapy Consortium, Imperial College, London SW3 6LR, United Kingdom.
authors.forename: Uta
authors.initials: U
authors.lastname: Griesenbach
authors.affiliation: Department of Gene Therapy and the U.K. Cystic Fibrosis Gene Therapy Consortium, Imperial College, London SW3 6LR, United Kingdom.
authors.forename: Kamila M
authors.initials: KM
authors.lastname: Pytel
authors.affiliation: Department of Gene Therapy and the U.K. Cystic Fibrosis Gene Therapy Consortium, Imperial College, London SW3 6LR, United Kingdom.
authors.forename: Eric W F W
authors.initials: EW
authors.lastname: Alton
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics* / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D009154:Mutation
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator
references.citation: Hum Gene Ther. 2007 Aug;18(8):726-32
references.pmid: 17685853
references.citation: J Clin Invest. 1997 Sep 15;100(6):1529-37
references.pmid: 9294121
references.citation: J Cyst Fibros. 2014 Jan;13(1):24-8
references.pmid: 24022019
references.citation: Mol Ther. 2013 Dec;21(12):2181-94
references.pmid: 23896725
references.citation: Science. 1989 Sep 8;245(4922):1059-65
references.pmid: 2772657
references.citation: Nature. 2010 Sep 16;467(7313):318-22
references.pmid: 20844535
references.citation: Hum Gene Ther. 1997 Jan 1;8(1):15-25
references.pmid: 8989991
references.citation: PLoS Biol. 2009 Jul;7(7):e1000155
references.pmid: 19621064
references.citation: J Virol. 2014 Mar;88(5):2991-3003
references.pmid: 24371066
references.citation: Lancet. 2014 Mar 29;383(9923):1138-46
references.pmid: 24412048
references.citation: Hum Gene Ther Clin Dev. 2014 Jun;25(2):97-107
references.pmid: 24865497
references.citation: Gene Ther. 1997 Mar;4(3):210-8
references.pmid: 9135734
references.citation: Science. 1989 Sep 8;245(4922):1066-73
references.pmid: 2475911
references.citation: Am J Respir Crit Care Med. 2012 Nov 1;186(9):846-56
references.pmid: 22955314
references.citation: J Virol. 2008 Aug;82(16):7875-85
references.pmid: 18524821
references.citation: Gene Ther. 1997 Mar;4(3):199-209
references.pmid: 9135733
references.citation: Mol Ther. 2009 Feb;17(2):285-93
references.pmid: 19034263
references.citation: J Gen Virol. 2009 Jan;90(Pt 1):1-20
references.pmid: 19088268
references.citation: Mol Ther. 2013 May;21(5):947-53
references.pmid: 23511247
references.citation: Annu Rev Med. 2007;58:157-70
references.pmid: 17217330
references.citation: Hum Gene Ther. 2001 May 1;12(7):751-61
references.pmid: 11339892
references.citation: Mol Ther. 2009 Feb;17(2):294-301
references.pmid: 19066597
references.citation: Mol Ther Nucleic Acids. 2012 Nov 27;1:e56
references.pmid: 23187455
references.citation: Am J Physiol Lung Cell Mol Physiol. 2014 Dec 15;307(12):L917-23
references.pmid: 25381027
references.citation: Biomaterials. 2013 Dec;34(38):10267-77
references.pmid: 24090839
references.citation: J Clin Invest. 1999 Nov;104(9):1245-55
references.pmid: 10545523
references.citation: J Virol. 2008 Nov;82(21):10684-92
references.pmid: 18768988
references.citation: Am Rev Respir Dis. 1986 Jul;134(1):49-56
references.pmid: 2425673
references.citation: Science. 2008 Sep 26;321(5897):1837-41
references.pmid: 18818360
references.citation: Int J Biochem Cell Biol. 2014 Jul;52:47-57
references.pmid: 24727426
references.citation: Biores Open Access. 2012 Jun;1(3):99-108
references.pmid: 23514673
references.citation: Mol Ther. 2003 May;7(5 Pt 1):649-58
references.pmid: 12718908
references.citation: Nat Genet. 1992 Sep;2(1):21-5
references.pmid: 1284642
references.citation: J Gene Med. 2004 Feb;6 Suppl 1:S164-71
references.pmid: 14978759
references.citation: J Biol Chem. 2009 Dec 18;284(51):35926-38
references.pmid: 19837664
references.citation: Viruses. 2010 Sep;2(9):1886-917
references.pmid: 21994713
references.citation: Hum Gene Ther. 2014 Nov;25(11):966-76
references.pmid: 25144316
references.citation: J Cyst Fibros. 2014 Dec;13(6):674-80
references.pmid: 25266159
references.citation: Nat Med. 2013 Jul;19(7):889-91
references.pmid: 23770691
references.citation: J Virol. 2006 Dec;80(24):12049-59
references.pmid: 17005667
references.citation: J Clin Invest. 2013 Jul;123(7):2994-3001
references.pmid: 23778142
references.citation: Hum Gene Ther. 2004 Dec;15(12):1255-69
references.pmid: 15684701
references.citation: Cell. 1993 Oct 22;75(2):207-16
references.pmid: 7691415
references.citation: Nat Med. 2015 Feb;21(2):121-31
references.pmid: 25654603
references.citation: Cell. 2010 Dec 10;143(6):911-23
references.pmid: 21145458
references.citation: Gene Ther. 2011 Oct;18(10):996-1005
references.pmid: 21512505
references.citation: Hum Gene Ther. 1995 Nov;6(11):1487-96
references.pmid: 8573621
references.citation: Clin Microbiol Rev. 2003 Apr;16(2):242-64
references.pmid: 12692097
references.citation: J Gene Med. 2005 Nov;7(11):1409-20
references.pmid: 15999396
references.citation: Am J Respir Cell Mol Biol. 2011 Jun;44(6):922-9
references.pmid: 20724552
references.citation: Hum Mol Genet. 2013 Oct 15;22(R1):R52-8
references.pmid: 23918661
references.citation: Nat Genet. 1993 Feb;3(2):151-6
references.pmid: 7684646
references.citation: Hum Gene Ther. 2002 Nov 1;13(16):1961-70
references.pmid: 12427306
references.citation: N Engl J Med. 1995 Sep 28;333(13):823-31
references.pmid: 7544439
references.citation: Am J Physiol Cell Physiol. 2010 Dec;299(6):C1222-33
references.pmid: 20926781
references.citation: Gene Ther. 2008 Apr;15(8):553-60
references.pmid: 18288209
references.citation: Hum Gene Ther Clin Dev. 2013 Jun;24(2):47-54
references.pmid: 23862696
references.citation: N Engl J Med. 2014 Nov 20;371(21):1994-2004
references.pmid: 25409372
references.citation: J Biol Chem. 1999 Apr 9;274(15):10219-26
references.pmid: 10187807
references.citation: Gene Ther. 2014 Jan;21(1):89-95
references.pmid: 24196086
references.citation: Pharmacol Ther. 2015 Jan;145:19-34
references.pmid: 24932877
references.citation: Gene Ther. 2011 Feb;18(2):182-8
references.pmid: 20962870
references.citation: J Biol Chem. 1993 Feb 15;268(5):3781-90
references.pmid: 7679117
references.citation: Hum Gene Ther. 2001 Jul 20;12(11):1383-94
references.pmid: 11485630
references.citation: N Engl J Med. 2011 Nov 3;365(18):1663-72
references.pmid: 22047557
references.citation: Nat Cell Biol. 2006 Sep;8(9):933-44
references.pmid: 16921366
references.citation: Hum Gene Ther. 2009 Mar;20(3):267-81
references.pmid: 19257851
references.citation: Science. 2013 Aug 23;341(6148):1233158
references.pmid: 23845948
references.citation: Mol Ther. 2000 Jan;1(1):105-14
references.pmid: 10933918
references.citation: Am J Respir Crit Care Med. 2005 May 1;171(9):1015-9
references.pmid: 15640364
references.citation: Am J Respir Cell Mol Biol. 1994 Nov;11(5):517-21
references.pmid: 7946381
references.citation: Cold Spring Harb Perspect Med. 2015;5(9):a017285
references.pmid: 25635059
references.citation: Mol Ther. 2014 Aug;22(8):1484-93
references.pmid: 24869933
references.citation: Cell Stem Cell. 2013 Dec 5;13(6):653-8
references.pmid: 24315439
references.citation: Gene Ther. 2012 Jun;19(6):649-58
references.pmid: 22357511
references.citation: Thorax. 2013 Jun;68(6):532-9
references.pmid: 23396354
references.citation: Mol Ther. 2010 Jun;18(6):1173-82
references.pmid: 20332767
references.citation: Nature. 2012 Jul 5;487(7405):109-13
references.pmid: 22763554
references.citation: Nat Biotechnol. 2008 May;26(5):549-51
references.pmid: 18438402
references.citation: J Clin Invest. 1996 Mar 15;97(6):1504-11
references.pmid: 8617884
references.citation: J Biol Chem. 2007 Oct 26;282(43):31422-8
references.pmid: 17724021
references.citation: Science. 1989 Sep 8;245(4922):1073-80
references.pmid: 2570460
references.citation: J Clin Invest. 1995 Mar;95(3):1377-82
references.pmid: 7533790
references.citation: Expert Opin Biol Ther. 2013 Jul;13(7):987-1011
references.pmid: 23590247
references.citation: Nat Genet. 1994 Sep;8(1):42-51
references.pmid: 7527271
references.citation: Mol Biol Cell. 2005 May;16(5):2154-67
references.pmid: 15716351
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15364-9
references.pmid: 14673110
references.citation: Gene Ther. 2000 Jul;7(13):1156-65
references.pmid: 10918483
references.citation: Lancet. 1999 Mar 20;353(9157):947-54
references.pmid: 10459902
references.citation: Science. 2013 Aug 23;341(6148):1233151
references.pmid: 23845947
references.citation: Mol Ther. 2012 Apr;20(4):699-708
references.pmid: 22273577
references.citation: J Virol. 2003 Feb;77(4):2607-14
references.pmid: 12551999
references.citation: Hum Gene Ther. 2001 Jul 20;12(11):1369-82
references.pmid: 11485629
references.citation: Hum Gene Ther. 1999 Dec 10;10(18):2973-85
references.pmid: 10609658
references.citation: Gene Ther. 2006 Mar;13(5):449-56
references.pmid: 16319950
references.citation: Nat Genet. 1992 Nov;2(3):240-8
references.pmid: 1285365
references.citation: Am J Respir Cell Mol Biol. 2005 May;32(5):404-10
references.pmid: 15695737
references.citation: Mol Ther. 2012 Jun;20(6):1108-15
references.pmid: 22371844
references.citation: Biochemistry. 2006 Aug 29;45(34):10260-9
references.pmid: 16922501
references.citation: Gene Ther. 2007 Oct;14(19):1371-9
references.pmid: 17597790
references.citation: J Clin Invest. 1992 May;89(5):1478-84
references.pmid: 1569186
references.citation: Mol Ther. 2010 Mar;18(3):594-600
references.pmid: 19826405
references.citation: Gene Ther. 2009 Dec;16(12):1416-28
references.pmid: 19727141
references.citation: Hum Gene Ther. 2010 Dec;21(12):1657-64
references.pmid: 20735256
references.citation: J Gene Med. 2013 Jan;15(1):51-62
references.pmid: 23319179
references.citation: Mol Ther. 2010 Jun;18(6):1165-72
references.pmid: 20372105
references.citation: Respir Res. 2010;11:84
references.pmid: 20569421
references.citation: Nat Med. 1995 Jan;1(1):39-46
references.pmid: 7584951
references.citation: Mol Ther. 2009 Dec;17(12):2067-77
references.pmid: 19603002
references.citation: J Clin Invest. 2008 May;118(5):1955-64
references.pmid: 18414684
references.citation: Lab Invest. 2000 Jun;80(6):857-68
references.pmid: 10879737
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L1123-30
references.pmid: 16085675