Targeting protein homeostasis in sporadic inclusion body myositis.
Targeting protein homeostasis in sporadic inclusion body myositis.
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DOI：
10.1126/scitranslmed.aad4583
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发表时间：
2016-03-23
影响因子：
17.1
通讯作者：
Greensmith L
中科院分区：
文献类型：
--
作者：
Ahmed M;Machado PM;Miller A;Spicer C;Herbelin L;He J;Noel J;Wang Y;McVey AL;Pasnoor M;Gallagher P;Statland J;Lu CH;Kalmar B;Brady S;Sethi H;Samandouras G;Parton M;Holton JL;Weston A;Collinson L;Taylor JP;Schiavo G;Hanna MG;Barohn RJ;Dimachkie MM;Greensmith L
散发性包涵体肌炎（sIBM）是50岁以上患者中最常见的严重肌病。以前的治疗试验针对sIBM的炎症特征，但都失败了。由于蛋白质稳态异常也可能在sIBM中发挥作用，因此我们测试了针对该疾病特征的影响。使用大鼠成肌细胞培养物，我们发现用Arimoclomol上调热休克反应减少了体外sIBM的关键病理标志物。此外，在发生包涵体肌病（IBM）的含Valosin突变蛋白VCP小鼠中，用Arimoclomol治疗改善了疾病病理学并改善了肌肉功能。因此，我们在一项以药物为先导的、随机、双盲、安慰剂对照、概念验证患者试验中评估了Arimoclomol的安全性和耐受性，并收集了探索性疗效数据，这些数据表明Arimoclomol是安全的，耐受性良好。尽管Arimoclomol在突变VCP小鼠中在体外和体内改善了一些IBM样病理学，但我们在该概念验证患者试验中没有看到统计学显著的疗效证据。
Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients over age 50. Previous therapeutic trials have targeted the inflammatory features of sIBM, but all have failed. Since 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 (IBM), treatment with Arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated the safety and tolerability of Arimoclomol in an investigator-lead, randomised, double-blind, placebo-controlled, proof-of-concept patient trial and gathered exploratory efficacy data which showed that Arimoclomol was safe and well tolerated. Although Arimoclomol improved some IBM-like pathology in vitro and in vivo in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in this proof of concept patient trial.
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DOI：
10.1196/annals.1391.032
发表时间：
2007-01-01
期刊：
STRESS RESPONSES IN BIOLOGY AND MEDICINE
影响因子：
--
作者：
Brown, Ian R.
通讯作者：
Brown, Ian R.
影响因子：
9.9
作者：
Badrising, UA;Maat-Schieman, M;Wintzen, AR
通讯作者：
Wintzen, AR
影响因子：
5
作者：
Greenberg, Steven A
通讯作者：
Greenberg, Steven A
影响因子：
14.5
作者：
Cox, Fieke M.;Titulaer, Maarten J.;Badrising, Umesh A.
通讯作者：
Badrising, Umesh A.
影响因子：
14.5
作者：
Benveniste, Olivier;Guiguet, Marguerite;Hilton-Jones, David
通讯作者：
Hilton-Jones, David