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Multiple sclerosis (MS) is the most common demyelinating disease. Despite the historical use of interferon-beta (IFN-β) for the treatment of patients with MS, concerns exist regarding the side effects of IFN-β. In this study, we designed a series of novel IFN-β fusion proteins containing galectin-9 (gal-9), which exerts immunosuppressive effects through the binding to its receptor on activated Th1 cells. We hypothesized that these fusion proteins would improve the therapeutic effects and reduce the side effects of IFN-β. The IFN-β-gal-9 fusion proteins showed less IFN-β biological activity on non-T cells than IFN-β alone. In vitro experiments using re-stimulated T cells isolated from mice with experimental autoimmune encephalomyelitis (EAE) showed that the IFN-β-gal-9 fusion proteins suppressed activated T cells more effectively than IFN-β. Moreover, in our in vivo experiments, the gene transfer of IFN-β-gal-9 fusion protein-expressing plasmid DNA into EAE mice showed beneficial therapeutic effects without cytopenia, a known side effect of IFN-β. In contrast, the gene transfer of IFN-β-expressing plasmid DNA induced a rapid decrease in the white blood cell count, despite its therapeutic effect. These results indicate that gene therapy using IFN-β-gal-9 fusion proteins is expected to be safe and effective for the treatment of MS.