Codelivery of NF-kappaB decoy-related oligodeoxynucleotide improves LPD-mediated systemic gene transfer.
A systemic gene delivery vector for LPD (cationic liposome-polycation-DNA) has been reported previously to transfect the pulmonary endothelium and holds promise for treating pulmonary diseases. However, the uptake of LPD by immune cells triggers a strong inflammatory response that is toxic to animals and limits transgene expression. In this study, LPD was used to codeliver phosphorothioate oligodeoxynucleotides (ODNs) containing an NF-kappaB consensus binding sequence with plasmid DNA carrying a reporter gene. Codelivery of a single-stranded kappaB ODN inhibited TNF-alpha induction by LPD-plasmid delivery and increased transgene expression in the lung in a dose-dependent manner. A similar effect was observed with the double-stranded ODN of the same sequence at twice the dose, and the complementary ODN (antisense) had no effect. Sequence mutation study suggested that the effect was sequence specific and these ODNs may achieve their effect through interaction with NF-kappaB family proteins in a decoy manner. In addition to enhancing gene transfer, these single-stranded ODNs formulated in LPD may be explored as anti-inflammatory agents.
Tan
Yadi
Y
Center for Pharmacogenetics, School of Pharmacy, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Zhang
Jing Shi
JS
Huang
Leaf
L
D000818:Animals; D001483:Base Sequence; D016384:Consensus Sequence / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008081:Liposomes / Q000008:administration & dosage; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000235:genetics*; D010957:Plasmids; D020218:Response Elements / Q000235:genetics*; D013379:Substrate Specificity; D013997:Time Factors; D019076:Transgenes / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D008081:Liposomes; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha