title: Targeting protein homeostasis in sporadic inclusion body myositis.
abstract: 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.
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Mhoriam
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Machado
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Miller
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Spicer
authors.affiliation: Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Herbelin
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Jianghua
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Janelle
authors.initials: J
authors.lastname: Noel
authors.affiliation: Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
authors.forename: April L
authors.initials: AL
authors.lastname: McVey
authors.affiliation: Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
authors.forename: Mamatha
authors.initials: M
authors.lastname: Pasnoor
authors.affiliation: Department of Health, Sport, and Exercise Science, The University of Kansas, Lawrence, KS 66045-7567, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Gallagher
authors.affiliation: Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Statland
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Ching-Hua
authors.initials: CH
authors.lastname: Lu
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Bernadett
authors.initials: B
authors.lastname: Kalmar
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Stefen
authors.initials: S
authors.lastname: Brady
authors.affiliation: Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, UCL Hospitals, Queen Square, London WC1N 3BG, UK.
authors.forename: Huma
authors.initials: H
authors.lastname: Sethi
authors.affiliation: Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, UCL Hospitals, Queen Square, London WC1N 3BG, UK.
authors.forename: George
authors.initials: G
authors.lastname: Samandouras
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Matt
authors.initials: M
authors.lastname: Parton
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.affiliation: The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Weston
authors.affiliation: The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Collinson
authors.affiliation: Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barohn
authors.affiliation: Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA. l.greensmith@ucl.ac.uk mdimachkie@kumc.edu.
authors.forename: Mazen M
authors.initials: MM
authors.lastname: Dimachkie
authors.affiliation: Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. l.greensmith@ucl.ac.uk mdimachkie@kumc.edu.
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002986:Clinical Trials as Topic; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D016896:Treatment Outcome; D000074405:Valosin Containing Protein
chemical_list: D016229:Amyloid beta-Peptides; D018797:Cell Cycle Proteins; D018840:HSP70 Heat-Shock Proteins; D006898:Hydroxylamines; D018836:Inflammation Mediators; D011506:Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; C000614180:Vcp protein, rat; C486387:arimoclomol