Treatment of experimental autoimmune encephalomyelitis using AAV gene therapy by blocking T cell costimulatory pathways

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by inflammation and demyelination. Presently, repeated relapses of MS necessitate long-term immune-regulatory therapy. Blocking the CD28-B7 and CD40-CD40L costimulatory pathways is an effective and synergistic method for the prevention and amelioration of clinical symptoms of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. In this study, to explore the efficacy and safety of MS gene therapy, we used adeno-associated virus (AAV) as a vector to deliver CTLA4immunoglobulin (Ig) or CD40-Ig on the EAE induced by myelin oligodendrocyte glycoprotein (MOG). Our results showed that a single administration of AAV8-CTLA4-Ig, either alone or with AAV8-CD40-Ig, protected mice from EAE and reversed disease progression. Decreased CD4(+) and CD8(+) T cell infiltration, inhibition of MOG antibody response, and downregulation of neuroinflammation were observed in mice receiving AAV, suggesting that autoimmunity was suppressed in EAE pathology. Moreover, no hematological or hepatic toxicity was observed in AAV-treated mice. Thus, compared with treatment with recombinant CTLA4-Ig (belatacept), AAV gene therapy could effectively control clinical symptoms and suppress autoimmunity in the long term. In summary, our study provides a potential therapeutic method for blocking T cell costimulation for the treatment of MS via gene therapy.