Targeting protein homeostasis in sporadic inclusion body myositis.
نویسندگان
چکیده
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.
منابع مشابه
Ongoing Developments in Sporadic Inclusion Body Myositis
Sporadic inclusion body myositis (IBM) is an acquired muscle disorder associated with ageing, for which there is no effective treatment. Ongoing developments include: genetic studies that may provide insights regarding the pathogenesis of IBM, improved histopathological markers, the description of a new IBM autoantibody, scrutiny of the diagnostic utility of clinical features and biomarkers, th...
متن کاملInclusion body myositis: new insights into pathogenesis.
PURPOSE OF REVIEW The pathogenesis of sporadic inclusion body myositis is complex and the disease has a relentless course. Recent observations regarding possible mechanisms of disease may provide targets for therapy. RECENT FINDINGS Evidence is strengthening that specific T-cell and B-cell responses are ongoing in skeletal muscle in sporadic inclusion body myositis and that cytokines and chem...
متن کاملInclusion-body myositis, a multifactorial muscle disease associated with aging: current concepts of pathogenesis.
PURPOSE OF REVIEW Sporadic inclusion-body myositis, the most common muscle disease of older persons, has no known cause or persistently beneficial treatment. The unfolding pathogenesis could lead to new treatment strategies and it is now of growing interest among clinicians and basic scientists. About 100 papers related to the subject were published in 2006 and the first part of 2007 (we cite o...
متن کاملInclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches.
Inclusion body myositis is the most common acquired muscle disease in older individuals, and its prevalence varies among countries and ethnic groups. The aetiology and pathogenesis of sporadic inclusion body myositis are still poorly understood; however genetic factors, ageing, and environmental triggers might all have a role. Unlike other inflammatory myopathies, sporadic inclusion body myosit...
متن کاملCalcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis
Sporadic inclusion body myositis (IBM) is the most common primary myopathy in the elderly, but its pathoetiology is still unclear. Perturbed myocellular calcium (Ca2+) homeostasis can exacerbate many of the factors proposed to mediate muscle degeneration in IBM, such as mitochondrial dysfunction, protein aggregation, and endoplasmic reticulum stress. Ca2+ dysregulation may plausibly be initiate...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Science translational medicine
دوره 8 331 شماره
صفحات -
تاریخ انتشار 2016