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Sendai virus-mediated CFTR gene transfer to the airway epithelium

Lookup NU author(s): Dr Burns Verdon, Professor Barry Argent, Dr Michael Gray

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Abstract

The potential for gene therapy to be an effective treatment for cystic fibrosis has been hampered by the limited gene transfer efficiency of current vectors. We have shown that recombinant Sendai virus (SeV) is highly efficient in mediating gene transfer to differentiated airway epithelial cells, because of its capacity to overcome the intra- and extracellular barriers known to limit gene delivery. Here, we have identified a novel method to allow the cystic fibrosis transmembrane conductance regulator (CFTR) cDNA sequence to be inserted within SeV (SeV-CFTR). Following in vitro transduction with SeV-CFTR, a chloride-selective current was observed using whole-cell and single-channel patch-clamp techniques. SeV-CFTR administration to the nasal epithelium of cystic fibrosis (CF) mice (CftrG551D and Cftrtm1UncTgN(FABPCFTR)#Jaw mice) led to partial correction of the CF chloride transport defect. In addition, when compared to a SeV control vector, a higher degree of inflammation and epithelial damage was found in the nasal epithelium of mice treated with SeV-CFTR. Second-generation transmission-incompetent F-deleted SeV-CFTR led to similar correction of the CF chloride transport defect in vivo as first-generation transmission-competent vectors. Further modifications to the vector or the host may make it easier to translate these studies into clinical trials of cystic fibrosis.


Publication metadata

Author(s): Ferrari S, Griesenbach U, Iida A, Farley R, Wright AM, Zhu J, Munkonge FM, Smith SN, You J, Ban H, Inoue M, Chan M, Singh C, Verdon B, Argent BE, Wainwright B, Jeffery PK, Geddes DM, Porteous DJ, Hyde SC, Gray MA, Hasegawa M, Alton EWFW

Publication type: Article

Publication status: Published

Journal: Gene Therapy

Year: 2007

Volume: 14

Issue: 19

Pages: 1371-1379

ISSN (print): 0969-7128

ISSN (electronic): 1476-5462

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/sj.gt.3302991

DOI: 10.1038/sj.gt.3302991

PubMed id: 17597790


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