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@article{Alton:2016:10.1136/thoraxjnl-2016-208406,
author = {Alton, EW and Beekman, JM and Boyd, AC and Brand, J and Carlon, MS and Connolly, MM and Chan, M and Conlon, S and Davidson, HE and Davies, JC and Davies, LA and Dekkers, JF and Doherty, A and Gea-Sorli, S and Gill, DR and Griesenbach, U and Hasegawa, M and Higgins, TE and Hironaka, T and Hyndman, L and McLachlan, G and Inoue, M and Hyde, SC and Innes, JA and Maher, TM and Moran, C and Meng, C and Paul-Smith, MC and Pringle, IA and Pytel, KM and Rodriguez-Martinez, A and Schmidt, AC and Stevenson, BJ and Sumner-Jones, SG and Toshner, R and Tsugumine, S and Wasowicz, MW and Zhu, J},
doi = {10.1136/thoraxjnl-2016-208406},
journal = {Thorax},
pages = {137--147},
title = {Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis},
url = {http://dx.doi.org/10.1136/thoraxjnl-2016-208406},
volume = {72},
year = {2016}
}

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TY  - JOUR
AB  - 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-pseudotype
AU  - Alton,EW
AU  - Beekman,JM
AU  - Boyd,AC
AU  - Brand,J
AU  - Carlon,MS
AU  - Connolly,MM
AU  - Chan,M
AU  - Conlon,S
AU  - Davidson,HE
AU  - Davies,JC
AU  - Davies,LA
AU  - Dekkers,JF
AU  - Doherty,A
AU  - Gea-Sorli,S
AU  - Gill,DR
AU  - Griesenbach,U
AU  - Hasegawa,M
AU  - Higgins,TE
AU  - Hironaka,T
AU  - Hyndman,L
AU  - McLachlan,G
AU  - Inoue,M
AU  - Hyde,SC
AU  - Innes,JA
AU  - Maher,TM
AU  - Moran,C
AU  - Meng,C
AU  - Paul-Smith,MC
AU  - Pringle,IA
AU  - Pytel,KM
AU  - Rodriguez-Martinez,A
AU  - Schmidt,AC
AU  - Stevenson,BJ
AU  - Sumner-Jones,SG
AU  - Toshner,R
AU  - Tsugumine,S
AU  - Wasowicz,MW
AU  - Zhu,J
DO  - 10.1136/thoraxjnl-2016-208406
EP  - 147
PY  - 2016///
SN  - 0040-6376
SP  - 137
TI  - Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis
T2  - Thorax
UR  - http://dx.doi.org/10.1136/thoraxjnl-2016-208406
UR  - http://www.ncbi.nlm.nih.gov/pubmed/27852956
UR  - http://hdl.handle.net/10044/1/43026
VL  - 72
ER  -

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