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S56 Moving lentiviral-based gene therapy into a first-in-man CF trial
  1. U Griesenbach1,
  2. EWFW Alton1,
  3. JM Beekman2,
  4. AC Boyd3,
  5. M Chan1,
  6. JC Davies1,
  7. LA Davies4,
  8. HE Davidson3,
  9. JF Dekkers5,
  10. S Gea-Sorli1,
  11. DR Gill4,
  12. M Hasegawa6,
  13. T Higgins1,
  14. L Hyndman3,
  15. G McLachlan7,
  16. M Inoue6,
  17. SC Hyde4,
  18. C Moran1,
  19. C Meng1,
  20. MC Paul-Smith1,
  21. IA Pringle4,
  22. KM Pytel1,
  23. A Rodriguez-Martinez1,
  24. BJ Stevenson3,
  25. S Tsugumine6
  1. 1Imperial College, London, UK
  2. 2Department of Pediatric Pulmonology, University Medical Centre, Utrecht, The Netherlands
  3. 3Medical Genetics, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK
  4. 4Gene Medicine Group, NDCLS, John Radcliffe Hospital, University of Oxford, Oxford, UK
  5. 5Laboratory of Translational Immunology, Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, The Netherlands
  6. 6DNAVEC Corporation, Tsukuba, Japan
  7. 7Developmental Biology Division, The Roslin Institute Roslin, Edinburgh, UK


The UK CF Gene Therapy Consortium has developed a pipeline of vectors to deliver CFTR into the airway epithelium. The first of these (plasmid/liposome complexes) recently completed a Phase IIb trial. Anticipating that increased efficiency of gene transfer will be required, we have developed an F/HN-pseudotyped lentivirus which is ~2 logs more efficient in lung gene transfer than non-viral vectors, a single administration lasts for the lifetime of a mouse, and can be repeatedly administered. This vector is targeted for a first-in-man study in 2016, and in preparation for this we have assessed (1) selection of the most efficient promoter/enhancer for lung gene transfer, (2) assessment of toxicity “benchmarked” against the leading non-viral formulation including mapping of integration sites, (3) determination of transduction efficiency which will be used to inform dose-ranging in the trial and characterisation of the cell types transduced by the vector, (4) understanding the impact of pre-existing and acquired anti-viral immunity on transduction efficiency and toxicity, (5) confirmation of CFTR expression and function in relevant models and (6) comparison of vector stability in a jet and single-pass mesh nebuliser. Data will be presented for each of these components, which we believe support progression into human studies. Trial design as well as a regulatory-compliant toxicology study will also be discussed.

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