Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis

Eric W.F.W. Alton, Jeffery M. Beekman, A. Christopher Boyd, June Brand, Marianne S. Carlon, Mary M. Connolly, Mario Chan, Sinead Conlon, Heather E. Davidson, Jane C. Davies, Lee A. Davies, Johanna F. Dekkers, Ann Doherty, Sabrina Gea-Sorli, Deborah R. Gill, Uta Griesenbach, Mamoru Hasegawa, Tracy E. Higgins, Takashi Hironaka, Laura HyndmanGerry McLachlan, Makoto Inoue, Stephen C. Hyde, J. Alastair Innes, Toby M. Maher, Caroline Moran, Cuixiang Meng, Michael C. Paul-Smith, Ian A. Pringle, Kamila M. Pytel, Andrea Rodriguez-Martinez, Alexander C. Schmidt, Barbara J. Stevenson, Stephanie G. Sumner-Jones, Richard Toshner, Shu Tsugumine, Marguerite W. Wasowicz, Jie Zhu

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

114 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)137-147
Aantal pagina's11
Nummer van het tijdschrift2
StatusGepubliceerd - 1 feb. 2017
Extern gepubliceerdJa


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