Targeting Protein Homeostasis in Sporadic Inclusion Body Myositis
Machado, Pedro M.
Noel-MacDonnell, Janelle Rose
McVey, April L.
Gallagher, Philip M.
Holton, Janice L.
Taylor, J. Paul
Hanna, Michael G.
Barohn, Richard J.
Dimachkie, Mazen M.
American Association for the Advancement of Science
Scholarly/refereed, author accepted manuscript
MetadataShow full item record
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.
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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