title: Prevention of adverse events of interferon γ gene therapy by gene delivery of interferon γ-heparin-binding domain fusion protein in mice.
abstract: Sustained gene delivery of interferon (IFN) γ can be an effective treatment, but our previous study showed high levels of IFNγ-induced adverse events, including the loss of body weight. These unwanted events could be reduced by target-specific delivery of IFNγ after in vivo gene transfer. To achieve this, we selected the heparin-binding domain (HBD) of extracellular superoxide dismutase as a molecule to anchor IFNγ to the cell surface. We designed three IFNγ derivatives, IFNγ-HBD1, IFNγ-HBD2, and IFNγ-HBD3, each of which had 1, 2, or 3 HBDs, respectively. Each plasmid-encoding fusion proteins was delivered to the liver, a model target in this study, by hydrodynamic tail vein injection. The serum concentration of IFNγ-HBD2 and IFNγ-HBD3 after gene delivery was lower than that of IFNγ or IFNγ-HBD1. Gene delivery of IFNγ-HBD2, but not of IFNγ-HBD3, effectively increased the mRNA expression of IFNγ-inducible genes in the liver, suggesting liver-specific distribution of IFNγ-HBD2. Gene delivery of IFNγ-HBD2-suppressed tumor growth in the liver as efficiently as that of IFNγ with much less symptoms of adverse effects. These results indicate that the adverse events of IFNγ gene transfer can be prevented by gene delivery of IFNγ-HBD2, a fusion protein with high cell surface affinity.
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism , Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ando
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism , Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism , Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism , Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism , Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto, Japan.
authors.forename: Makiya
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Department of Molecular Microbiology, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism , Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Takakura