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    Targeting Protein Homeostasis in Sporadic Inclusion Body Myositis

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    Issue Date
    2016-03-23
    Author
    Ahmed, Mhoriam
    Machado, Pedro M.
    Miller, Adrian
    Spicer, Charlotte
    Herbelin, Laura
    He, Jianghua
    Noel-MacDonnell, Janelle Rose
    Wang, Yunxia
    McVey, April L.
    Pasnoor, Mamatha
    Gallagher, Philip M.
    Statland, Jeffrey
    Lu, Ching-Hua
    Kalmar, Bernadett
    Brady, Stefen
    Sethi, Huma
    Samandouras, George
    Parton, Matt
    Holton, Janice L.
    Weston, Anne
    Collinson, Lucy
    Taylor, J. Paul
    Schiavo, Giampietro
    Hanna, Michael G.
    Barohn, Richard J.
    Dimachkie, Mazen M.
    Greensmith, Linda
    Publisher
    American Association for the Advancement of Science
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
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    Abstract
    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.
    URI
    http://hdl.handle.net/1808/22036
    DOI
    https://doi.org/10.1126/scitranslmed.aad4583
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    • Health, Sport & Exercise Sciences Scholarly Works [113]
    Citation
    Mhoriam Ahmed, Pedro M. Machado, Adrian Miller, Charlotte Spicer, Laura Herbelin, Jianghua He, Janelle Noel, Yunxia Wang, April L. McVey, Mamatha Pasnoor, Philip Gallagher, Jeffrey Statland, Ching-Hua Lu, Bernadett Kalmar, Stefen Brady, Huma Sethi, George Samandouras, Matt Parton, Janice L. Holton, Anne Weston, Lucy Collinson, J. Paul Taylor, Giampietro Schiavo, Michael G. Hanna, Richard J. Barohn, Mazen M. Dimachkie, Linda Greensmith Sci Transl Med. Author manuscript; available in PMC 2016 Sep 30. Published in final edited form as: Sci Transl Med. 2016 Mar 23; 8(331): 331ra41. doi: 10.1126/scitranslmed.aad4583

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    KU Libraries
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    785-864-8983

    KU Libraries
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    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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