TY - JOUR
T1 - Ex vivo and in vivo lentivirus-mediated transduction of airway epithelial progenitor cells
AU - Leoni, Giulia
AU - Wasowicz, Marguerite Y.
AU - Chan, Mario
AU - Meng, Cuixiang
AU - Farley, Raymond
AU - Brody, Steven L.
AU - Inoue, Makoto
AU - Hasegawa, Mamoru
AU - Alton, Eric W.F.W.
AU - Griesenbach, Uta
N1 - Publisher Copyright:
© 2015 Bentham Science Publishers.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
KW - Cystic fibrosis
KW - Gene therapy
KW - Lentivirus
KW - Polidocanol
KW - Progenitor basal cells
UR - http://www.scopus.com/inward/record.url?scp=84947942537&partnerID=8YFLogxK
U2 - 10.2174/1566523215666151016123625
DO - 10.2174/1566523215666151016123625
M3 - Article
C2 - 26471068
AN - SCOPUS:84947942537
SN - 1566-5232
VL - 15
SP - 581
EP - 590
JO - Current gene therapy
JF - Current gene therapy
IS - 6
ER -