Comparison of Gene Expression Efficiency and Innate Immune Response Induced by Ad Vector and Lipoplex
Abstract
Vectors for gene expression are the essential tools for both gene therapy and basic research. There are two groups of gene therapy vectors, viral and non-viral vectors. At present, toxicity triggered by vectors is one of the major concerns for clinical trials. In general, non-viral vectors, such as plasmid DNA-cationic liposome complex (lipoplex), are thought to be safer than viral vectors, such as adenovirus (Ad) vector, although lipoplex is less efficient in term of gene expression than the Ad vector. However, there has been no study directly comparing the gene expression efficiency and safety of viral and non-viral vectors. Here, we present evidence that the Ad vector shows much more efficient gene expression and is safer than lipoplex, at least with respect to the innate immune response. After being systemically administered to mice, the Ad vector showed a transduction efficiency that was 2 to 5 log orders higher than that of lipoplex, depending on the organ. On the other hand, surprisingly, the administration of lipoplex produced a greater amount of inflammatory cytokines such as interleukin-6, interleukin-12, and tumor necrosis factor-alpha than did the administration of the Ad vector, whereas a comparable level of hepatotoxicity was induced by these vectors. The production of inflammatory cytokines induced by the injection of lipoplex was reduced when the CpG motifs were removed completely from plasmid DNA. Thus, care should be taken to ensure the innate immune response induced by gene therapy vectors, especially lipoplex.
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Immune responses induced by non-viral vectors have been reported.
“Additionally, as elaborated in the following sections of this review, immune responses induced by non-viral vectors have also been reported [19].”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [19]
Cites
A Toll-like receptor recognizes bacterial DNA
Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., et al. (2000) · Nature · doi:10.1038/35047123 · Cited by 6,491 · see citing works
Innate immune recognition of viral infection
Kawai, T., & Akira, S. (2006) · Nature Immunology · doi:10.1038/ni1303 · Cited by 1,899 · see citing works
Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics
Kay, M., Glorioso, J., & Naldini, L. (2001) · Nature Medicine · doi:10.1038/83324 · Cited by 1,444 · see citing works
Gene Therapy Progress and Prospects: Nonviral vectors
Niidome, T., & Huang, L. (2002) · Gene Therapy · doi:10.1038/sj.gt.3301923 · Cited by 967 · see citing works
The polypeptides of adenovirus
Maizel, J. V., WHITE, D. O., & Scharff, M. D. (1968) · Virology · doi:10.1016/0042-6822(68)90121-9 · Cited by 883 · see citing works
In vivo gene transfer via intravenous administration of cationic lipid–protamine–DNA (LPD) complexes
Li, S., & Huang, L. (1997) · Gene Therapy · doi:10.1038/sj.gt.3300482 · Cited by 478 · see citing works
Adenoviruses as Gene-Delivery Vehicles
Wilson, J. M. (1996) · New England Journal of Medicine · doi:10.1056/nejm199605023341809 · Cited by 478 · see citing works
Molecular basis of the inflammatory response to adenovirus vectors
Liu, Q., & Muruve, D. A. (2003) · Gene Therapy · doi:10.1038/sj.gt.3302036 · Cited by 432 · see citing works
Adenovirus Binding to Blood Factors Results in Liver Cell Infection and Hepatotoxicity
Shayakhmetov, D. M., Gaggar, A., Ni, S., Li, Z.-Y., & Lieber, A. (2005) · Journal of Virology · doi:10.1128/jvi.79.12.7478-7491.2005 · Cited by 429 · see citing works
The Innate Immune Response to Adenovirus Vectors
Muruve, D. A. (2004) · Human Gene Therapy · doi:10.1089/hum.2004.15.1157 · Cited by 408 · see citing works
Zhang, Y., Chirmule, N. B., Gao, G., Qian, R., Croyle, M. A., Joshi, B., Tazelaar, J., & Wilson, J. M. (2001) · Molecular Therapy · doi:10.1006/mthe.2001.0329 · Cited by 377 · see citing works
Hemmi, H., Kaisho, T., Takeda, K., & Akira, S. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.6.3059 · Cited by 338 · see citing works
Efficient Construction of a Recombinant Adenovirus Vector by an Improved In Vitro Ligation Method
Mizuguchi, H., & Kay, M. A. (1998) · Human Gene Therapy · doi:10.1089/hum.1998.9.17-2577 · Cited by 338 · see citing works
Self-citationA Simple Method for Constructing E1- and E1/E4-Deleted Recombinant Adenoviral Vectors
Mizuguchi, H., & Kay, M. A. (1999) · Human Gene Therapy · doi:10.1089/10430349950017374 · Cited by 261 · see citing works
Self-citationLiu, F., Qi, H., Huang, L., & Liu, D. (1997) · Gene Therapy · doi:10.1038/sj.gt.3300424 · Cited by 247 · see citing works
Proteoglycans Mediate Cationic Liposome-DNA Complex-based Gene Delivery in Vitro and in Vivo
Mounkes, L. C., Zhong, W., Cipres-Palacin, G., Heath, T. D., & Debs, R. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.40.26164 · Cited by 245 · see citing works
Cationic Liposome-mediated Intravenous Gene Delivery
Liu, Y., Liggitt, D., Zhong, W., Tu, G., Gaensler, K. M. L., & Debs, R. J. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.42.24864 · Cited by 231 · see citing works
Mizuguchi, H., Koizumi, N., Hosono, T., Utoguchi, N., Watanabe, Y., Kay, M. A., & Hayakawa, T. (2001) · Gene Therapy · doi:10.1038/sj.gt.3301453 · Cited by 225 · see citing works
Self-citationLi, S., Wu, S.-P., Whitmore, M., Loeffert, E., Wang, L., Watkins, S. C., Pitt, B. R., & Huang, L. (1999) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1999.276.5.l796 · Cited by 225 · see citing works
Innate immune recognition of, and regulation by, DNA
Ishii, K. J., & Akira, S. (2006) · Trends in Immunology · doi:10.1016/j.it.2006.09.002 · Cited by 222 · see citing works
LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth
Whitmore, M., Li, S., & Huang, L. (1999) · Gene Therapy · doi:10.1038/sj.gt.3301026 · Cited by 199 · see citing works
Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity
ZHANG, J., LIU, F., & Huang, L. (2005) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2004.12.004 · Cited by 195 · see citing works
In Vivo Characteristics of Cationic Liposomes as Delivery Vectors for Gene Therapy
Audouy, S. A. L., de Leij, L. F. M. H., Hoekstra, D., & Molema, G. (2002) · Pharmaceutical Research · doi:10.1023/a:1020989709019 · Cited by 189 · see citing works
Sakurai, F., Inoue, R., Nishino, Y., Okuda, A., Matsumoto, O., Taga, T., Yamashita, F., Takakura, Y., & Hashida, M. (2000) · Journal of Controlled Release · doi:10.1016/s0168-3659(99)00280-1 · Cited by 169 · see citing works
Self-citationMizuguchi, H., & Hayakawa, T. (2004) · Human Gene Therapy · doi:10.1089/hum.2004.15.1034 · Cited by 159 · see citing works
Self-citationBacterial DNA as immune cell activator
Lipford, G. B. (1998) · Trends in Microbiology · doi:10.1016/s0966-842x(98)01408-5 · Cited by 119 · see citing works
The role of CpG motifs in immunostimulation and gene therapy
Scheule, R. K. (2000) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00090-9 · Cited by 109 · see citing works
Osaka, G., Carey, K. D., Cuthbertson, A. G. S., et al. (1996) · Journal of Pharmaceutical Sciences · doi:10.1021/js9504494 · Cited by 104 · see citing works
Contribution of Plasmid DNA to Hepatotoxicity after Systemic Administration of Lipoplexes
Loisel, S., Gall, C., Doucet, L., Férec, C., & Floch, V. (2001) · Human Gene Therapy · doi:10.1089/104303401300057405 · Cited by 98 · see citing works
Yasuda, K., Ogawa, Y., Yamane, I., Nishikawa, M., & Takakura, Y. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0204089 · Cited by 92 · see citing works
Zhao, H., Hemmi, H., Akira, S., Cheng, S. H., Scheule, R. K., & Yew, N. S. (2004) · Molecular Therapy · doi:10.1016/j.ymthe.2003.11.012 · Cited by 85 · see citing works
Uyechi, L. S., Gagné, L., Thurston, G., & Szoka, F. C. (2001) · Gene Therapy · doi:10.1038/sj.gt.3301461 · Cited by 84 · see citing works
Non‐immunostimulatory nonviral vectors
Liu, F., Shollenberger, L. M., & Huang, L. (2004) · The FASEB Journal · doi:10.1096/fj.04-2187fje · Cited by 70 · see citing works
Fletcher, S., Ahmad, A., Pérouzel, É., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm0507227 · Cited by 61 · see citing works
Adenoviral vectors—How to use them in cancer gene therapy?
Majhen, D., & Ambriović‐Ristov, A. (2006) · Virus Research · doi:10.1016/j.virusres.2006.02.001 · Cited by 59 · see citing works
Toxicity of Cationic Lipid‐DNA Complexes
Yew, N. S., & Scheule, R. K. (2005) · Advances in genetics · doi:10.1016/s0065-2660(05)53007-4 · Cited by 54 · see citing works
Yasuda, K., Kawano, H., Yamane, I., et al. (2004) · Immunology · doi:10.1111/j.1365-2567.2004.01814.x · Cited by 44 · see citing works
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Xu, L., & Anchordoquy, T. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22243 · Cited by 209 · see citing works
Ren, D., Fisson, S., Dalkara, D., & Ail, D. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14091973 · Cited by 52 · see citing works
- Authors
- Sakurai, H., Sakurai, F., Kawabata, K., Sasaki, T., Koizumi, N., Huang, H., Tashiro, K., Kurachi, S., Nakagawa, S., & Mizuguchi, H.
- Affiliations
- National Institute of Biomedical Innovation (JP)
- The University of Osaka (JP)
- Corresponding author
- Mizuguchi, Hiroyuki
- ORCID
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 117
- Issue
- 3
- Pages
- 430-437
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2063743438
- Cited by
- 40
- References
- 37
- Citations by year
- 2025: 1 · 2022: 1 · 2021: 1 · 2017: 1 · 2016: 4 · 2014: 1 · 2013: 1 · 2012: 4
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- adenoviral vector, lipoplexes, non-viral gene therapy vectors, gene expression efficiency, innate immune response, inflammatory cytokines, hepatotoxicity, CpG motifs, plasmid DNA, transduction efficiency, vector safety
- MeSH terms
- Adenoviridae, Quaternary Ammonium Compounds, Animals, Drug Carriers, Excipients, Fatty Acids, Monounsaturated, Female, Genetic Vectors, Immunity, Innate, Liposomes, Liver, Mice, Inbred C57BL, Plasmids, Transduction, Genetic, Tumor Necrosis Factor-alpha, Interleukin-6, Gene Expression, Cytokines, Paraffin Embedding, Interleukin-12, Mice, Chemical and Drug Induced Liver Injury
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