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Activation of TLR9 by incorporated pDNA within PEG-coated lipoplex enhances anti-PEG IgM production

Gene Therapy volume 21, pages 593–598 (2014)Cite this article

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Abstract

Cationic liposome represents a promising alternative to viral vectors for the delivery of therapeutic genes. For in vivo use, surface modification of the liposome with polyethylene glycol (PEG) is frequently applied to achieve gene-expression in the targeted tissue. However, we have reported that PEG-coated liposomes have induced anti-PEG IgM, which has caused subsequent doses of PEG-coated liposome to be rapidly cleared from blood circulation, and the complexation of pDNA electrostatically associated with liposome surface has enhanced this antibody response. In this study, we investigated how a Toll-like receptor (TLR) might enhance anti-PEG IgM production. PEG-coated pDNA-lipoplex (PDCL) was injected into either wild type, MyD88 (all TLR adaptor protein, independent of TLR3) knock out (KO) or TLR9 KO mice, and the anti-PEG IgM production levels were detected. Attenuated anti-PEG IgM production following the injection of PDCL was observed in both MyD88 and TLR9 KO mice compared to wild type mice, probably due to the abolished induction of cytokines in both MyD88 and TLR9 KO mice. Our results suggest that TLR, exclusively TLR9, signaling plays a potential role in the enhanced anti-PEG IgM production following the injection of PDCL. This result may have important implications for the design and development of an efficient PEG-coated non-viral gene vector.

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Acknowledgements

The authors thank Mr JL McDonald for his kind assistance in writing the manuscript. This study was supported, in part, by the Takeda Science Foundation and by a Grant-in-Aid for Scientific Research (B) (23390012) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan

    Y Hashimoto, Y Uehara, A S Abu Lila, T Ishida & H Kiwada

  2. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt

    A S Abu Lila

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  1. Y Hashimoto
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  3. A S Abu Lila
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Correspondence to T Ishida.

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Hashimoto, Y., Uehara, Y., Abu Lila, A. et al. Activation of TLR9 by incorporated pDNA within PEG-coated lipoplex enhances anti-PEG IgM production. Gene Ther 21, 593–598 (2014). https://doi.org/10.1038/gt.2014.32

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