title: Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis.
abstract: We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air-liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and 'benchmarked' against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90-100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F/HN-pseudotyped lentiviral vector into a first-in-man CF trial in 2017.
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Eric W F W
authors.initials: EW
authors.lastname: Alton
authors.affiliation: Department of Pediatric Pulmonology, Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Beekman
authors.affiliation: Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: A Christopher
authors.initials: AC
authors.lastname: Boyd
authors.affiliation: Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK.|Lung Pathology Unit, Department of Airway Disease Infection, NHLI, Imperial College London, London, UK.
authors.forename: June
authors.initials: J
authors.lastname: Brand
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Brussels, Belgium.
authors.forename: Marianne S
authors.initials: MS
authors.lastname: Carlon
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford, UK.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Connolly
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Chan
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Sinead
authors.initials: S
authors.lastname: Conlon
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Davidson
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Davies
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford, UK.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Davies
authors.affiliation: Department of Pediatric Pulmonology, Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Johanna F
authors.initials: JF
authors.lastname: Dekkers
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Doherty
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Gea-Sorli
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford, UK.
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Gill
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Uta
authors.initials: U
authors.lastname: Griesenbach
authors.affiliation: ID Pharme Co. Ltd. (DNAVEC Center), Tsukuba, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Higgins
authors.affiliation: ID Pharme Co. Ltd. (DNAVEC Center), Tsukuba, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hironaka
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Hyndman
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Roslin Institute & R(D)SVS, University of Edinburgh, Midlothian, UK.
authors.forename: Gerry
authors.initials: G
authors.lastname: McLachlan
authors.affiliation: ID Pharme Co. Ltd. (DNAVEC Center), Tsukuba, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford, UK.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Hyde
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK.
authors.forename: J Alastair
authors.initials: JA
authors.lastname: Innes
authors.affiliation: Fibrosis Research Group, Inflammation, Repair & Development Section, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College, London, UK.
authors.forename: Toby M
authors.initials: TM
authors.lastname: Maher
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Moran
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Cuixiang
authors.initials: C
authors.lastname: Meng
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Paul-Smith
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford, UK.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Pringle
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Kamila M
authors.initials: KM
authors.lastname: Pytel
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rodriguez-Martinez
authors.affiliation: Ave Leopold Wiener, Brussels, Belgium.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Schmidt
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Stevenson
authors.affiliation: UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.|Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford, UK.
authors.forename: Stephanie G
authors.initials: SG
authors.lastname: Sumner-Jones
authors.affiliation: Fibrosis Research Group, Inflammation, Repair & Development Section, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Toshner
authors.affiliation: ID Pharme Co. Ltd. (DNAVEC Center), Tsukuba, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Tsugumine
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.|UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK.
authors.forename: Marguerite W
authors.initials: MW
authors.lastname: Wasowicz
authors.affiliation: Lung Pathology Unit, Department of Airway Disease Infection, NHLI, Imperial College London, London, UK.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics* / Q000628:therapy*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D020648:Peptide Elongation Factor 1; D011401:Promoter Regions, Genetic
chemical_list: D020648:Peptide Elongation Factor 1
keywords: Cystic Fibrosis