Effective therapy of polymyositis in mice via selective inhibition of the immunoproteasome

Polymyositis (PM) is a chronic autoimmune inflammatory myopathy resulting in muscle weakness. The limited approved therapies and their poor efficacy contribute to its comorbidity. We investigated the therapeutic use of ONX 0914 and KZR-616, selective inhibitors of the immunoproteasome, in C protein-induced myositis (CIM), a mouse model of PM that closely resembles the human disease. Diseased mice (day 13 postimmunization) were treated with 10 mg/kg ONX 0914, KZR-616, or vehicle on alternate days until day 28. Endpoints included muscle strength assessed by a grip strength meter, serum creatine kinase activity, histology, and immunohistochemistry analysis. Treatment with ONX 0914 or KZR-616 prevented the loss of grip strength in mice after CIM induction, while vehicle-treated animals displayed progressive muscle weakness. Immunoproteasome inhibition lowered PM-associated leukocyte infiltration of the muscle and prevented increased serum creatine kinase levels. LMP7-deficient mice were resistant to CIM induction, as they showed no alterations in grip strength or creatine kinase (CK) levels or muscular alterations. In conclusion, selective inhibition of the immunoproteasome displays therapeutic efficacy in a preclinical mouse model of PM with suppression of muscle inflammation and preservation of muscle strength. Positive results from this study support the rationale for using KZR-616 in clinical studies.