Developing mAb-siRNA conjugate for therapy of myasthenia gravis

The autoimmune myasthenia gravis is a disease of muscle fatigue caused by neuromuscular junction dysfunction, mediated primarily by an autoantibody against the acetylcholine receptor. In a novel study, we have recently shown that combined treatment of BAFF Receptor (BR)- and B cell maturation antigen (BCMA)- specific monoclonal antibody and siRNA (mAb-siRNA) conjugates markedly reduced autoantibody production and improve clinical disease in experimental mouse model of myasthenia. BR is critical for mature B cell function that differentiate into plasma cells, and BCMA is preferentially expressed in overactive plasma cells that produce high levels of autoantibody. In this proposal we propose to continue the study to further develop the conjugates, test the conjugates in humanized mice, convey a mechanistic study of their therapeutic effects, and determine any non-target adverse genetic effects. The results might have a major impact in developing a highly effective therapy for myasthenia gravis to significantly improve or ameliorate the disease.