Enhancement of adenovirus-mediated gene transfer to the airways by DEAE dextran and sodium caprate in vivo

• Published in: Molecular therapy Vol. 7; no. 1; pp. 19 - 26
• Main Authors: Gregory, Lisa G, Harbottle, Richard P, Lawrence, Lorraine, Knapton, Holly J, Themis, Michael, Coutelle, Charles
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2003; Elsevier Limited
• Subjects: Adenoviridae - genetics; adenovirus; Adenoviruses; airways; Animals; apical gene delivery; Cell Line; Cytoskeleton; DEAE dextran; Decanoic Acids - chemistry; Dextrans; Egtazic Acid - chemistry; Female; Gene therapy; Gene Transfer Techniques; Humans; Infections; Investigations; Kinases; lung; Mice; Micelles; Permeability; Proteins; Sodium; sodium caprate; Toxicity; Trachea - metabolism; Transduction, Genetic; Transgenes; Vectors (Biology); sodium caprate; lung; apical gene delivery; adenovirus; airways; gene therapy; DEAE dextran
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/S1525-0016(02)00021-7

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 β-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.