title: 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.
authors.affiliation: Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Osaka, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Sakurai
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sakurai
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawabata
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Naoya
authors.initials: N
authors.lastname: Koizumi
authors.forename: Haiying
authors.initials: H
authors.lastname: Huang
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Tashiro
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Kurachi
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D004337:Drug Carriers; D005079:Excipients; D005229:Fatty Acids, Monounsaturated; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects; D007113:Immunity, Innate / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008081:Liposomes; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D016612:Paraffin Embedding; D010957:Plasmids / Q000737:chemistry / Q000235:genetics; D000644:Quaternary Ammonium Compounds; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D004337:Drug Carriers; D005079:Excipients; D005229:Fatty Acids, Monounsaturated; D015850:Interleukin-6; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane