A defective nontransmissible recombinant Sendai virus mediates efficient gene transfer to airway epithelium in vivo.
Recombinant Sendai virus (SeV)-mediated gene transfer to differentiated airway epithelial cells has shown to be very efficient, because of its ability to overcome the intra- and extracellular barriers known to limit gene delivery. However, this virus is transmission competent and therefore unlikely to be suitable for use in clinical trials. A nontransmissible, replication-competent recombinant SeV has recently been developed by deleting the envelope Fusion (F) protein gene (SeV/DeltaF). Here we show that SeV/DeltaF is able to mediate beta-galactosidase reporter gene transfer to the respiratory tract of mice in vivo, as well as to human nasal epithelial cells in vitro. Further, in an ex vivo model of differentiated airway epithelium, SeV/DeltaF gene transfer was not importantly inhibited by native mucus. When compared to the transmission-competent SeV in vivo, no difference in gene expression was observed at the time of peak expression. The development of an F-defective nontransmissible SeV, which can still efficiently mediate gene transfer to the airway epithelium, represents the first important step towards the use of a cytoplasmic RNA viral vector in clinical trials of gene therapy.
Department of Gene Therapy, National Heart & Lung Institute, Imperial College Faculty of Medicine, London, UK.
S
S
Ferrari
U
U
Griesenbach
T
T
Shiraki-Iida
T
T
Shu
T
T
Hironaka
X
X
Hou
J
J
Williams
J
J
Zhu
P K
PK
Jeffery
D M
DM
Geddes
M
M
Hasegawa
E W F W
EW
Alton
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000628:therapy*; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus; D009297:Nasal Mucosa / Q000201:enzymology*; D029082:Sendai virus / Q000235:genetics*; D012756:Sheep; D014132:Trachea / Q000201:enzymology; D014161:Transduction, Genetic / Q000379:methods*; D014759:Viral Envelope Proteins / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics
D014759:Viral Envelope Proteins; D001616:beta-Galactosidase