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

Abstract

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.

Immunoproteasome inhibition attenuates experimental psoriasis

“…Hematoxylin-eosin sections were prepared as in ( 22 ). For immunofluorescence staining, the samples were flash-frozen in liquid nitrogen and embedded into anOptimal cutting temperature compound (OCT) medium.…”

“…Blood was collected by cardiac puncture. The analysis of IL-17A, IL-6 and TNF (ThermoFisher Scientific) was performed as in ( 22 ).…”

“…Immunoproteasome inhibition is a promising strategy in reducing IL-23 secretion and suppressing Th17 cell development ( 18 ). Irreversible inhibition of the LMP2/LMP7 subunits of the immunoproteasome via treatment with ONX 0914 has been demonstrated to ameliorate several inflammatory diseases ( 19 – 22 ).…”

Valosin-containing protein (VCP/p97) inhibition reduces viral clearance and induces toxicity associated with muscular damage

“…Immunoblotting was performed as described in [28]. The antibodies used were Ubiquitin (FK2, #BML-PW8810-0100), from Enzo Life Science or Bip (C50B12, #3177), IκBα (N-terminal Antigen, L35A5, #4814) and phospho-elF2α (Ser51, #9721) from Cell Signaling.…”

Proteasome composition in immune cells implies special immune‐cell‐specific immunoproteasome function

“…[24]). In recent years, the immunoproteasome has evolved to be an attractive drug target for several diseases such as rheumatoid arthritis [15], inflammatory bowel disease [25,26], systemic lupus erythematosus [27,28], multiple sclerosis [16,29], polymyositis [30], psoriasis [31], and cancers [12,[32][33][34]. KZR-616, an LMP7/2-selective inhibitor, is currently being tested in clinical trials for the treatment of rheumatic diseases [28,35,36].…”