Therapeutic potential of immunoproteasome inhibition in Duchenne muscular dystrophy

DMD arose from mutation of dystrophin protein determining loss of muscle force and inflammation . Emerging data from several laboratories demonstrated that immunoproteasomes exert a plethora of functions, in addition to the best-known immunological one. As they were found in skeletal muscles as a regulators of skeletal muscle differentiation, they were characterized in dystrophic mice, where their increased expression was related to the oxidative stress of dystrophic muscles. Taken together with the evidence that the transformation of the standard proteasome in the immunoproteasome is regulated by the action of different cytokines that are normally up-regulated into dystrophic environment, we suggested that the immunoproteasome could exert an important role in modulating the development of muscle and in controlling the inflammation in DMD patients. According to the fact that the inhibition of the immunoproteasome could be theoretically driven by steroids, the main therapy for DMD, we employed a highly specific inhibitor, – known to modulate cytokine production and to ameliorate the pathological phenotype of autoimmune diseases. This way, we decreased the rate of inflammation into dystrophic muscles by reducing activated lymphocytes but allowing the development of myogenic regulatory T-cells. More importantly, we demonstrate that - by interfering with MHC-I peptide presentation pathway - we acted specifically against anti-dystrophin activated lymphocytes. Auto-reactive lymphocytes arose from rare revertant dytrophin expressing fibers which prime T-cell response in the periphery, impeding the success of gene therapy. Taking into account these data, we suggested that the immunoproteasome could be a feasible pharmacological target for DMD.