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

Eric WFW. Alton, Jeffery M. Beekman, A. Christopher Boyd, June Brand, Marianne S. Carlon, Mary M. Connolly, Mario Chan, Sinead Conlon, Heather 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, James 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 Stevenson, Stephanie G. Sumner-Jones, Richard Toshner, Shu Tsugumine, Marguerite W. Wasowicz, Jie Zhu

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

We have recently shown that non-viral gene therapy can stabilise the decline of lung function in cystic fibrosis (CF) patients. However, the effect was modest, and more potent gene transfer agents are still required. F/HN-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in pre-clinical models. In preparation for a first-in-man CF trial using the lentiviral vector we have undertaken key translational pre-clinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air liquid interface cultures to select the lead candidate; 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 (hCEF) consisting of the elongation factor 1 promoter and the CMV enhancer was most efficacious in both murine lungs and human air liquid interface 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 progression of the F/HN pseudotyped lentiviral vector into a first-in-man CF trial in 2017.
Original languageEnglish
Pages (from-to)137-147
Issue number2
Early online date16 Nov 2016
Publication statusPublished - Feb 2017

Keywords / Materials (for Non-textual outputs)

  • Cystic fibrosis
  • gene therapy
  • gene transfer
  • lentivirus
  • viral vector


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