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Managing the airway defect in cystic fibrosis

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1U. Griesenbach, 2K. Mitomo, 2M. Inoue, 1L. Somerton, 1C. Meng, 2T. Tabata, 2Y. Ueda, 3G. Frankel, 1R. Farley, 1C. Singh, 1M. Chan, 1F. Munkonge, 1A. Brum, 1S. Xenariou, 1S. Escudero-Garcia, 2M. Hasegawa, 1E. W. F. W. Alton. 1Department of Gene Therapy, Imperial College at the National Heart and Lung Institute and The UK Cysstic Fibrosis Gene Therapy Consortium, London, UK, 2DNAVEC Corporation, Tsukuba, Ibaraki, Japan, 3Division of Cell and Molecular Biology, Imperial College London, London, UK

Gene therapy for cystic fibrosis (CF) is making encouraging progress into clinical trials. However, further improvements in transduction efficiency are desired. To develop a novel gene transfer vector that is improved and truly effective for CF gene therapy, a simian immunodeficiency virus (SIV) was pseudotyped with envelope proteins from Sendai virus (SeV), which is known to transduce unconditioned airway epithelial cells efficiently from the apical side. This novel vector was evaluated in vivo and in vitro directed towards CF gene therapy. Here we show that (1) we can produce relevant titres of an SIV vector pseudotyped with SeV envelope proteins for in vivo use; (2) this vector can transduce the respiratory epithelium of the murine nose in vivo at levels that may be relevant for clinical benefit in CF; (3) this can be achieved in a single formulation, and without the need for preconditioning; (4) expression can last for 15 months; (5) readministration is feasible; (6) the vector can transduce human air–liquid interface cultures; and (7) functional CFTR (cystic fibrosis transmembrane conductance regulator) chloride channels can be generated in vitro. Our data suggest that this lentiviral vector may provide a step change in airway transduction efficiency relevant to a clinical programme of gene therapy …

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