A key challenge in pulmonary gene therapy for cystic fibrosis is to provide long-term correction
of the genetic defect. This may be achievable by targeting airway epithelial stem/progenitor
cells with an integrating vector. Here, we evaluated the ability of a lentiviral vector, derived from the
simian immunodeficiency virus and pseudotyped with F and HN envelope proteins from Sendai virus,
to transduce progenitor basal cells of the mouse nasal airways. We first transduced basal cell-enriched
cultures ex vivo and confirmed efficient transduction of cytokeratin-5 positive cells. We next asked whether progenitor
cells could be transduced in vivo. We evaluated the transduction efficiency in mice pretreated by intranasal administration
of polidocanol to expose the progenitor cell layer. Compared to control mice, polidocanol treated mice demonstrated a
significant increase in the number of transduced basal cells at 3 and 14 days post vector administration. At 14 days, the
epithelium of treated mice contained clusters (4 to 8 adjacent cells) of well differentiated ciliated, as well as basal cells
suggesting a clonal expansion. These results indicate that our lentiviral vector can transduce progenitor basal cells in vivo,
although transduction required denudation of the surface epithelium prior to vector administration.
Keywords: Cystic fibrosis, Gene therapy, Lentivirus, Progenitor basal cells, Polidocanol.
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