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Cystic fibrosis
Original article
Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis
  1. Eric W F W Alton1,2,
  2. Jeffery M Beekman3,
  3. A Christopher Boyd4,2,
  4. June Brand4,5,
  5. Marianne S Carlon6,
  6. Mary M Connolly2,7,
  7. Mario Chan1,2,
  8. Sinead Conlon1,2,
  9. Heather E Davidson2,4,
  10. Jane C Davies1,2,
  11. Lee A Davies2,7,
  12. Johanna F Dekkers3,
  13. Ann Doherty2,4,
  14. Sabrina Gea-Sorli1,2,
  15. Deborah R Gill2,7,
  16. Uta Griesenbach1,2,
  17. Mamoru Hasegawa8,
  18. Tracy E Higgins1,2,
  19. Takashi Hironaka8,
  20. Laura Hyndman2,4,
  21. Gerry McLachlan2,9,
  22. Makoto Inoue8,
  23. Stephen C Hyde2,7,
  24. J Alastair Innes2,4,
  25. Toby M Maher10,
  26. Caroline Moran1,2,
  27. Cuixiang Meng1,2,
  28. Michael C Paul-Smith1,2,
  29. Ian A Pringle2,7,
  30. Kamila M Pytel1,2,
  31. Andrea Rodriguez-Martinez1,2,
  32. Alexander C Schmidt11,
  33. Barbara J Stevenson2,4,
  34. Stephanie G Sumner-Jones2,7,
  35. Richard Toshner10,
  36. Shu Tsugumine8,
  37. Marguerite W Wasowicz1,2,
  38. Jie Zhu5
  1. 1Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK
  2. 2UK Cystic Fibrosis Gene Therapy Consortium, Oxford, UK
  3. 3Department of Pediatric Pulmonology, Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands
  4. 4Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK
  5. 5Lung Pathology Unit, Department of Airway Disease Infection, NHLI, Imperial College London, London, UK
  6. 6Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Brussels, Belgium
  7. 7Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford, UK
  8. 8ID Pharme Co. Ltd. (DNAVEC Center), Tsukuba, Japan
  9. 9Roslin Institute & R(D)SVS, University of Edinburgh, Midlothian, UK
  10. 10Fibrosis Research Group, Inflammation, Repair & Development Section, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College, London, UK
  11. 11Ave Leopold Wiener, Brussels, Belgium
  1. Correspondence to Professor Uta Griesenbach, Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London SW3 6LR, UK; u.griesenbach{at}imperial.ac.uk Dr Chris Boyd, The Centre for Genomic and Experimental medicine, IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK; Chris.Boyd{at}ed.ac.uk. Professor Deborah Gill, Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford OX3 9DU, UK; Deborah.gill{at}ndcls.ox.ac.uk

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.

  • Cystic Fibrosis

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/thoraxjnl-2016-208406

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    Footnotes

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.