Research ArticleMYOPATHY

Targeting protein homeostasis in sporadic inclusion body myositis

Science Translational Medicine  23 Mar 2016:
Vol. 8, Issue 331, pp. 331ra41
DOI: 10.1126/scitranslmed.aad4583

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Targeting protein dyshomeostasis in myopathy

Sporadic inclusion body myositis (sIBM) is a debilitating adult myopathy that is difficult to treat. Although both inflammation and protein dyshomeostasis have been implicated in sIBM pathogenesis, treatments have only targeted the inflammatory component, and all have failed in clinical trials. In a new study, Ahmed et al. tested the effects of targeting protein dyshomeostasis using arimoclomol, a co-inducer of the heat shock response. In rat myoblast cell culture, arimoclomol reduced key pathological features of IBM. In mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. The authors then treated a small number of sIBM patients with arimoclomol and showed that it was safe and well tolerated.

Abstract

Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients more than 50 years of age. Previous therapeutic trials have targeted the inflammatory features of sIBM but all have failed. Because protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated arimoclomol in an investigator-led, randomized, double-blind, placebo-controlled, proof-of-concept trial in sIBM patients and showed that arimoclomol was safe and well tolerated. Although arimoclomol improved some IBM-like pathology in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in the proof-of-concept patient trial.

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