Enhancement of adenovirus-mediated gene transfer to the airways by DEAE dextran and sodium caprate in vivo.
Gene transfer to the trachea and airways by adenoviral vectors is limited by the basolateral localization of viral receptors, resulting in relatively low levels of transduction. Modification of paracellular permeability by sodium caprate, which opens tight junctions, enhances gene transfer from the apical side of cultured human airway epithelial cells. Based on this observation we investigated whether Na-caprate could also increase gene transfer when applied to the luminal surface of the airway epithelia in vivo and compared these results with EGTA, which has previously been shown to enhance adenovirus transduction. Transgene expression in the trachea and upper airways was increased 25-fold by a 10-min pretreatment with 50 mM Na-caprate, corresponding to a 3-fold improvement over EGTA. In the more peripheral airways EGTA had no effect, whereas expression of beta-gal was increased 3-fold by Na-caprate. When the adenovirus was complexed with DEAE dextran, transduction of the airway epithelia after Na-caprate pretreatment was increased 45-fold over virus alone. In conclusion, Na-caprate facilitates gene transfer to airway epithelia, particularly when adenovirus is complexed with DEAE dextran, and may in future be used in a clinical setting to enhance the efficiency of vectors for gene therapy of cystic fibrosis via airway delivery.
Gregory
Lisa G
LG
Gene Therapy Research Group, Department of Cell and Molecular Biology, Imperial College, London SW7 2AZ, United Kingdom. l.gregory@ic.ac.uk
Harbottle
Richard P
RP
Lawrence
Lorraine
L
Knapton
Holly J
HJ
Themis
Michael
M
Coutelle
Charles
C
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D003652:Decanoic Acids / Q000737:chemistry; D003911:Dextrans; D004533:Egtazic Acid / Q000737:chemistry; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D008823:Micelles; D014132:Trachea / Q000378:metabolism*; D014161:Transduction, Genetic; D019076:Transgenes
D003652:Decanoic Acids; D003911:Dextrans; D008823:Micelles; C031071:decanoic acid; D004533:Egtazic Acid