Amelioration of Experimental Autoimmune Encephalomyelitis in Mice by Interferon-Beta Gene Therapy, Using a Long-Term Expression Plasmid Vector

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Repeated injections of the interferon-β (IFN-β) protein are required for relapse prevention therapy in patients with MS. IFN-β gene transfer can be an alternative treatment that continuously supplies IFN-β protein to the patient without requiring repeated injections. In a previous study, we constructed a novel long-term IFN-β-expressing plasmid vector (pMx-IFN-β). In the present study, we examined whether gene transfer of pMx-IFN-β could be effective for the treatment of MS in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Seven days after injection of the EAE-inducing peptide, the EAE mice received hydrodynamic injections pMx-IFN-β. The severity of EAE symptoms in the pMx-IFN-β-treated mice was significantly lower for 1 month than that observed in the untreated mice. An evaluation of blood-brain barrier (BBB) function, using Evans Blue, showed that injection of pMx-IFN-β suppressed the BBB disruptions normally observed in EAE mice, while BBB disruptions remained evident in the untreated EAE mice. Histological analysis showed fewer invasive inflammatory cells in the spinal cords of the pMx-IFN-β-treated mice than in the spinal cords of the other mice. Serum interferon gamma protein (IFN-γ) concentrations in the pMx-IFN-β-treated mice were significantly lower than that in the untreated mice, indicating that IFN-β gene transfer suppressed the production of IFN-γ from pathogenic T cells. These results indicate that IFN-β transgene expression by single administration of the pMx-IFN-β can be an effective long-term treatment for MS.

Keywords: experimental autoimmune encephalomyelitis; interferon-β; long-term expression; multiple sclerosis; plasmid DNA.