Abstract
Pulmonary delivery of plasmid DNA (pDNA)/cationic liposome complexes is associated with an acute unmethylated CG dinucleotide (CpG)-mediated inflammatory response and brief duration of transgene expression. We demonstrate that retention of even a single CpG in pDNA is sufficient to elicit an inflammatory response, whereas CpG-free pDNA vectors do not. Using a CpG-free pDNA expression vector, we achieved sustained (≥56 d) in vivo transgene expression in the absence of lung inflammation.
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Acknowledgements
This work was funded by a grant from the UK Cystic Fibrosis Trust to the UK CF Gene Therapy Consortium.
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S.C.H., I.A.P. and D.R.G. conceived the study, performed the research, interpreted the results and prepared the manuscript. S.C.H., I.A.P., S.A., A.E.L., L.A.D., A.V., G.N.-A., A.-M.G., R.P.B., S.G.S.-J., M.C., H.L., D.N.S., F.M.M. and D.R.G. contributed to the construction and/or testing of the pDNA vectors. N.S.Y., S.H.C., A.C.B., J.C.D., U.G., D.J.P., D.N.S., F.M.M. and E.W.F.W.A. provided useful discussion.
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S.C.H, I.A.P, A.E.L and D.R.G hold intellectual property in the fourth-generation zero-CpG vectors described in the paper.
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Hyde, S., Pringle, I., Abdullah, S. et al. CpG-free plasmids confer reduced inflammation and sustained pulmonary gene expression. Nat Biotechnol 26, 549–551 (2008). https://doi.org/10.1038/nbt1399
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DOI: https://doi.org/10.1038/nbt1399
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