期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 8, 期 331, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aad4583
关键词
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资金
- Arthritis Research UK [19255]
- MRC Centre for Neuromuscular Diseases grant [G0601943]
- Kansas University Neurology Department Ziegler grant
- Kansas University GCRC CReFF (General Clinical Research Centre Clinical Research Feasibility Funding) grant
- Wellcome Trust [107116/Z/15/Z]
- Brain Research Trust
- Rosetrees Trust
- Stoneygate Trust
- European Community's Seventh Framework Programme (FP7)
- MRC Studentship
- Cancer Research UK
- MRC
- BBSRC (UK Biotechnology and Biological Sciences Research Council)
- EPSRC (Engineering and Physical Sciences Research Council) [MR/K01580X/1]
- National Institute for Health Research (NIHR) Rare Diseases Translational Research Collaboration (RD TRC)
- NIHR University College London Hospitals (UCLH) Biomedical Research Centre (BRC)
- Institutional Clinical and Translational Science Award
- NIH/NCATS (National Center for Advancing Translational Sciences) grant [UL1TR000001]
- MRC [G0601943, G0800674, MR/K000608/1] Funding Source: UKRI
- Brain Research UK [WAT13181] Funding Source: researchfish
- Medical Research Council [1351287, G0601943, G0800674, MR/K000608/1, G0601943B, MR/K000608/1B] Funding Source: researchfish
- Rosetrees Trust [M249-F1] Funding Source: researchfish
- The Francis Crick Institute [10004] Funding Source: researchfish
- Versus Arthritis [19255] Funding Source: researchfish
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, doubleblind, 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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