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Research Article
MYOPATHY

Targeting protein homeostasis in sporadic inclusion body myositis

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 [email protected], and Linda Greensmith [email protected]
Science Translational Medicine • 23 Mar 2016 • Vol 8, Issue 331 • p. 331ra41 • DOI: 10.1126/scitranslmed.aad4583
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Targeting protein dyshomeostasis in myopathy

Sporadic inclusion body myositis (sIBM) is a debilitating adult myopathy that is difficult to treat. Although both inflammation and protein dyshomeostasis have been implicated in sIBM pathogenesis, treatments have only targeted the inflammatory component, and all have failed in clinical trials. In a new study, Ahmed et al. tested the effects of targeting protein dyshomeostasis using arimoclomol, a co-inducer of the heat shock response. In rat myoblast cell culture, arimoclomol reduced key pathological features of IBM. In mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. The authors then treated a small number of sIBM patients with arimoclomol and showed that it was safe and well tolerated.

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.
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Supplementary Material

Summary

Materials and Methods
Fig. S1. Overexpression of β-APP and exposure to inflammatory mediators induce sIBM-like pathology in cultured myocytes.
Fig. S2. Mutant VCP mice show further signs of pathology.
Fig. S3. Consort diagram of the patients participating in the clinical trial.
Table S1. Baseline characteristics of the study population.
Table S2. Summary of all adverse events over the course of 1 year.
Table S3. Mean changes (±SD) in secondary outcome measures throughout the study period.
Movie S1. Low-magnification serial block-face scanning electron microscopy of arimoclomol-treated and untreated mutant VCP mouse muscle.
Movie S2. High-magnification serial block-face scanning electron microscopy of wild-type VCP mouse muscle.
Movie S3. High-magnification serial block-face scanning electron microscopy of untreated mutant VCP mouse muscle.
Movie S4. High-magnification serial block-face scanning electron microscopy of arimoclomol-treated mutant VCP mouse muscle.
References (59, 60)

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REFERENCES AND NOTES

1
Dimachkie M. M., Barohn R. J., Inclusion body myositis. Curr. Neurol. Neurosci. Rep. 13, 321 (2013).
2
Machado P., Brady S., Hanna M. G., Update in inclusion body myositis. Curr. Opin. Rheumatol. 25, 763–771 (2013).
3
Amato A. A., Gronseth G. S., Jackson C. E., Wolfe G. I., Katz J. S., Bryan W. W., Barohn R. J., Inclusion body myositis: Clinical and pathological boundaries. Ann. Neurol. 40, 581–586 (1996).
4
Amato A. A., Barohn R. J., Evaluation and treatment of inflammatory myopathies. J. Neurol. Neurosurg. Psychiatry 80, 1060–1068 (2009).
5
Cox F. M., Titulaer M. J., Sont J. K., Wintzen A. R., Verschuuren J. J. G. M., Badrising U. A., A 12-year follow-up in sporadic inclusion body myositis: An end stage with major disabilities. Brain 134 (Pt. 11), 3167–3175 (2011).
6
Benveniste O., Guiguet M., Freebody J., Dubourg O., Squier W., Maisonobe T., Stojkovic T., Leite M. I., Allenbach Y., Herson S., Brady S., Eymard B., Hilton-Jones D., Long-term observational study of sporadic inclusion body myositis. Brain 134 (Pt. 11), 3176–3184 (2011).
7
Cortese A., Machado P., Morrow J., Dewar L., Hiscock A., Miller A., Brady S., Hilton-Jones D., Parton M., Hanna M. G., Longitudinal observational study of sporadic inclusion body myositis: Implications for clinical trials. Neuromuscul. Disord. 23, 404–412 (2013).
8
Badrising U. A., Maat-Schieman M., van Duinen S. G., Breedveld F., van Doorn P., van Engelen B., van den Hoogen F., Hoogendijk J., Höweler C., de Jager A., Jennekens F., Koehler P., van der Leeuw H., de Visser M., Verschuuren J. J., Wintzen A. R., Epidemiology of inclusion body myositis in the Netherlands: A nationwide study. Neurology 55, 1385–1388 (2000).
9
Phillips B. A., Zilko P. J., Mastaglia F. L., Prevalence of sporadic inclusion body myositis in Western Australia. Muscle Nerve 23, 970–972 (2000).
10
Felice K. J., North W. A., Inclusion body myositis in Connecticut: Observations in 35 patients during an 8-year period. Medicine 80, 320–327 (2001).
11
Wilson F. C., Ytterberg S. R., St. Sauver J. L., Reed A. M., Epidemiology of sporadic inclusion body myositis and polymyositis in Olmsted County, Minnesota. J. Rheumatol. 35, 445–447 (2008).
12
Needham M., Corbett A., Day T., Christiansen F., Fabian V., Mastaglia F. L., Prevalence of sporadic inclusion body myositis and factors contributing to delayed diagnosis. J. Clin. Neurosci. 15, 1350–1353 (2008).
13
Shamim E. A., Rider L. G., Pandey J. P., O’Hanlon T. P., Jara L. J., Samayoa E. A., Burgos-Vargas R., Vazquez-Mellado J., Alcocer-Varela J., Salazar-Paramo M., Kutzbach A. G., Malley J. D., Targoff I. N., Garcia-De La Torre I., Miller F. W., Differences in idiopathic inflammatory myopathy phenotypes and genotypes between Mesoamerican Mestizos and North American Caucasians: Ethnogeographic influences in the genetics and clinical expression of myositis. Arthritis Rheum. 46, 1885–1893 (2002).
14
Greenberg S. A., Theories of the pathogenesis of inclusion body myositis. Curr. Rheumatol. Rep. 12, 221–228 (2010).
15
Dalakas M. C., Pathogenesis and therapies of immune-mediated myopathies. Autoimmun. Rev. 11, 203–206 (2012).
16
Greenberg S. A., Inclusion body myositis. Curr. Opin. Rheumatol. 23, 574–578 (2011).
17
Askanas V., Engel W. K., Inclusion-body myositis, a multifactorial muscle disease associated with aging: Current concepts of pathogenesis. Curr. Opin. Rheumatol. 19, 550–559 (2007).
18
Needham M., Mastaglia F. L., Inclusion body myositis: Current pathogenetic concepts and diagnostic and therapeutic approaches. Lancet Neurol. 6, 620–631 (2007).
19
Salajegheh M., Pinkus J. L., Taylor J. P., Amato A. A., Nazareno R., Baloh R. H., Greenberg S. A., Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis. Muscle Nerve 40, 19–31 (2009).
20
Weihl C. C., Temiz P., Miller S. E., Watts G., Smith C., Forman M., Hanson P. I., Kimonis V., Pestronk A., TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 79, 1186–1189 (2008).
21
Askanas V., Engel W. K., Inclusion-body myositis: A myodegenerative conformational disorder associated with Aβ, protein misfolding, and proteasome inhibition. Neurology 66 (Suppl. 1), S39–S48 (2006).
22
Nogalska A., Terracciano C., D’Agostino C., Engel W. K., Askanas V., p62/SQSTM1 is overexpressed and prominently accumulated in inclusions of sporadic inclusion-body myositis muscle fibers, and can help differentiating it from polymyositis and dermatomyositis. Acta Neuropathol. 118, 407–413 (2009).
23
McFerrin J., Engel W. K., Askanas V., Impaired innervation of cultured human muscle overexpressing βAPP experimentally and genetically: Relevance to inclusion-body myopathies. Neuroreport 9, 3201–3205 (1998).
24
Askanas V., McFerrin J., Baqué S., Alvarez R. B., Sarkozi E., Engel W. K., Transfer of β-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultured normal human muscle. Proc. Natl. Acad. Sci. U.S.A. 93, 1314–1319 (1996).
25
Moussa C. E.-H., Fu Q., Kumar P., Shtifman A., Lopez J. R., Allen P. D., LaFerla F., Weinberg D., Magrane J., Aprahamian T., Walsh K., Rosen K. M., Querfurth H. W., Transgenic expression of β-APP in fast-twitch skeletal muscle leads to calcium dyshomeostasis and IBM-like pathology. FASEB J. 20, 2165–2167 (2006).
26
Schmidt J., Barthel K., Zschüntzsch J., Muth I. E., Swindle E. J., Hombach A., Sehmisch S., Wrede A., Lühder F., Gold R., Dalakas M. C., Nitric oxide stress in sporadic inclusion body myositis muscle fibres: Inhibition of inducible nitric oxide synthase prevents interleukin-1β-induced accumulation of β-amyloid and cell death. Brain 135 (Pt. 4), 1102–1114 (2012).
27
Schmidt J., Barthel K., Wrede A., Salajegheh M., Bähr M., Dalakas M. C., Interrelation of inflammation and APP in sIBM: IL-1β induces accumulation of β-amyloid in skeletal muscle. Brain 131, 1228–1240 (2008).
28
Amato A. A., Barohn R. J., Jackson C. E., Pappert E. J., Sahenk Z., Kissel J. T., Inclusion body myositis: Treatment with intravenous immunoglobulin. Neurology 44, 1516–1518 (1994).
29
Dalakas M. C., Koffman B., Fujii M., Spector S., Sivakumar K., Cupler E., A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology 56, 323–327 (2001).
30
The Muscle Study Group, Randomized pilot trial of high-dose βINF-1a in patients with inclusion body myositis. Neurology 63, 718–720 (2004).
31
Breithaupt M., Schmidt J., Update on treatment of inclusion body myositis. Curr. Rheumatol. Rep. 15, 329 (2013).
32
Douglas P. M., Cyr D. M., Interplay between protein homeostasis networks in protein aggregation and proteotoxicity. Biopolymers 93, 229–236 (2010).
33
Kopito R. R., Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10, 524–530 (2000).
34
Brown I. R., Heat shock proteins and protection of the nervous system. Ann. N. Y. Acad. Sci. 1113, 147–158 (2007).
35
Kalmar B., Greensmith L., Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects. Cell. Mol. Biol. Lett. 14, 319–335 (2009).
36
Kieran D., Kalmar B., Dick J. R. T., Riddoch-Contreras J., Burnstock G., Greensmith L., Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat. Med. 10, 402–405 (2004).
37
Kalmar B., Burnstock G., Vrbová G., Urbanics R., Csermely P., Greensmith L., Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats. Exp. Neurol. 176, 87–97 (2002).
38
Kalmar B., Greensmith L., Malcangio M., McMahon S. B., Csermely P., Burnstock G., The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury. Exp. Neurol. 184, 636–647 (2003).
39
Hargitai J., Lewis H., Boros I., Rácz T., Fiser A., Kurucz I., Benjamin I., Vígh L., Pénzes Z., Csermely P., Latchman D. S., Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1. Biochem. Biophys. Res. Commun. 307, 689–695 (2003).
40
Vígh L., Literáti P. N., Horváth I., Török Z., Balogh G., Glatz A., Kovács E., Boros I., Ferdinándy P., Parkas B., Jaszlits L., Jednákovits A., Korányi L., Maresca B., Bimoclomol: A nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects. Nat. Med. 3, 1150–1154 (1997).
41
Custer S. K., Neumann M., Lu H., Wright A. C., Taylor J. P., Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone. Hum. Mol. Genet. 19, 1741–1755 (2010).
42
Rohn T. T., Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer’s disease. Brain Res. 1228, 189–198 (2008).
43
Kuner P., Schubenel R., Hertel C., β-amyloid binds to p57NTR and activates NFκB in human neuroblastoma cells. J. Neurosci. Res. 54, 798–804 (1998).
44
Feinstein D. L., Galea E., Aquino D. A., Li G. C., Xu H., Reis D. J., Heat shock protein 70 suppresses astroglial-inducible nitric-oxide synthase expression by decreasing NFκB activation. J. Biol. Chem. 271, 17724–17732 (1996).
45
Njemini R., Bautmans I., Onyema O. O., Van Puyvelde K., Demanet C., Mets T., Circulating heat shock protein 70 in health, aging and disease. BMC Immunol. 12, 24 (2011).
46
Henstridge D. C., Forbes J. M., Penfold S. A., Formosa M. F., Dougherty S., Gasser A., de Courten M. P., Cooper M. E., Kingwell B. A., de Courten B., The relationship between heat shock protein 72 expression in skeletal muscle and insulin sensitivity is dependent on adiposity. Metabolism 59, 1556–1561 (2010).
47
Morton J. P., Kayani A. C., McArdle A., Drust B., The exercise-induced stress response of skeletal muscle, with specific emphasis on humans. Sports Med. 39, 643–662 (2009).
48
Lanka V., Wieland S., Barber J., Cudkowicz M., Arimoclomol: A potential therapy under development for ALS. Expert Opin. Investig. Drugs 18, 1907–1918 (2009).
49
Kürthy M., Mogyorósi T., Nagy K., Kukorelli T., Jednákovits A., Tálosi L., Bíró K., Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models. Ann. N. Y. Acad. Sci. 967, 482–489 (2002).
50
Kalmar B., Novoselov S., Gray A., Cheetham M. E., Margulis B., Greensmith L., Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1G93A mouse model of ALS. J. Neurochem. 107, 339–350 (2008).
51
Malik B., Nirmalananthan N., Gray A. L., La Spada A. R., Hanna M. G., Greensmith L., Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: Implications for therapy. Brain 136 (Pt. 3), 926–943 (2013).
52
Cudkowicz M. E., Shefner J. M., Simpson E., Grasso D., Yu H., Zhang H., Shui A., Schoenfeld D., Brown R. H., Wieland S., Barber J. R.Northeast ALS Consortium, Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis. Muscle Nerve 38, 837–844 (2008).
53
Tawil R., Griggs R. C., Inclusion body myositis. Curr. Opin. Rheumatol. 14, 653–657 (2002).
54
Griggs R. C., Askanas V., DiMauro S., Engel A., Karpati G., Mendell J. R., Rowland L. P., Inclusion body myositis and myopathies. Ann. Neurol. 38, 705–713 (1995).
55
Jackson C. E., Barohn R. J., Gronseth G., Pandya S., Herbelin L., Inclusion body myositis functional rating scale: A reliable and valid measure of disease severity. Muscle Nerve 37, 473–476 (2008).
56
Morrow J. M., Ramdharry G. M., Machado P., Burns T., Amato A., Barohn R., Phillips L., Seyedsadjadi R., Joshi A., Dimachkie M., Gwathmey K., Herbelin L., Solorzano G., Hanna M., Rasch analysis of the IBMFRS. Muscle Nerve 48 (Suppl. 1), S2–S3 (2013).
57
The Muscle Study Group, Randomized pilot trial of βINF1a (Avonex) in patients with inclusion body myositis. Neurology 57, 1566–1570 (2001).
58
Rose M. R., McDermott M. P., Thornton C. A., Palenski C., Martens W. B., Griggs R. C., A prospective natural history study of inclusion body myositis: Implications for clinical trials. Neurology 57, 548–550 (2001).
59
T. J. Deerinck, E. A. Bushong, A. Thor, M. H. Ellisman, NCMIR methods for 3D EM: A new protocol for preparation of biological specimens for serial block face scanning electron microscopy. Available from http://ncmir.ucsd.edu/sbfsem-protocol.pdf (2010).
60
Kieran D., Greensmith L., Inhibition of calpains, by treatment with leupeptin, improves motoneuron survival and muscle function in models of motoneuron degeneration. Neuroscience 125, 427–439 (2004).

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Science Translational Medicine
Volume 8 | Issue 331
March 2016

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Copyright © 2016, American Association for the Advancement of Science.

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Received: 17 September 2015
Accepted: 4 March 2016

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Acknowledgments

We thank the participants who enrolled in this intensive study and the KIT (Keep In Touch) and Myositis UK support groups. The following clinicians, research nurses, coordinators, and technicians contributed substantially to the trial: M. Walsh, M. Michaels, F. Raja, A. Dick, K. Latinis, L. Dewar, G. Barreto, and I. Skorupinska. We thank Orphazyme ApS and CytRx for providing drug and placebo. Funding: This work was funded by Arthritis Research UK (ref. no. 19255), MRC Centre for Neuromuscular Diseases grant (G0601943), Kansas University Neurology Department Ziegler grant, Kansas University GCRC CReFF (General Clinical Research Centre Clinical Research Feasibility Funding) grant, and the Wellcome Trust (107116/Z/15/Z) (G. Schiavo). L.G. is the Graham Watts Senior Research Fellow, supported by the Brain Research Trust, Rosetrees Trust, The Stoneygate Trust, and funded by the European Community’s Seventh Framework Programme (FP7/2007–2013). C.S. is the recipient of an MRC Studentship. L.C. and A.W. are funded by Cancer Research UK, the MRC, BBSRC (UK Biotechnology and Biological Sciences Research Council), and EPSRC (Engineering and Physical Sciences Research Council) under grant award MR/K01580X/1 to L.C. and P. O’Toole (York University). P.M.M. reports funding from the National Institute for Health Research (NIHR) Rare Diseases Translational Research Collaboration (RD TRC) and from the NIHR University College London Hospitals (UCLH) Biomedical Research Centre (BRC). The views expressed are those of the author and not necessarily those of the UK National Health Service (NHS), the NIHR, or the Department of Health. This project was also supported by an Institutional Clinical and Translational Science Award and NIH/NCATS (National Center for Advancing Translational Sciences) grant (UL1TR000001). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Author contributions: M.A., A.M., and L.G. designed the in vitro experiments. M.A. and L.G. designed the in vivo experiments, and M.A. and C.S. performed the experiments and the data analyses. J.P.T. generated and characterized the VCP mice. P.M.M., A.M., L.H., Y.W., A.L.M., M.P., P.G., J.S., S.B., M.P., J.H., M.G.H., R.J.B., M.M.D., and L.G. designed the clinical trial. P.M.M. performed the clinical trial assessments in the UK. L.H., Y.W., A.L.M., M.P., R.J.B., and M.M.D. performed the clinical trial assessments in the United States. J.H. and J.N. conducted data analyses of the trial data. M.M.D., A.L.M., H.S., and G. Samandouras performed the trial muscle biopsies. J.L.H. performed muscle histopathology of patient biopsies from the trial. C.-H.L. and B.K. performed the HSP measurements in the trial muscle tissue. A.W. and L.C. carried out the electron microscopy analyses, and G. Schiavo undertook their interpretation. M.G.H., R.J.B., and M.M.D. supervised the clinical trial. L.G. supervised the in vitro cell models and in vivo preclinical trial experiments and HSP measurements in the muscle tissue. M.A., P.M.M., C.S., and L.G. wrote the drafts of the manuscript and all authors provided scientific input to the manuscript. All authors read and approved the final version of the manuscript. Competing interests: L.G. became an unpaid consultant to Orphazyme ApS (the owner of arimoclomol) after completing this study. The other authors declare that they have no competing interests.

Authors

Affiliations

Mhoriam Ahmed*
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.
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Pedro M. Machado*
Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK.
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Adrian Miller*
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.
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Charlotte Spicer*
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.
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Laura Herbelin
Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
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Jianghua He
Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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Janelle Noel
Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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Yunxia Wang
Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
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April L. McVey
Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
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Mamatha Pasnoor
Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
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Philip Gallagher
Department of Health, Sport, and Exercise Science, The University of Kansas, Lawrence, KS 66045–7567, USA.
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Jeffrey Statland
Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
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Ching-Hua Lu
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.
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Bernadett Kalmar
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.
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Stefen Brady
Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK.
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Huma Sethi
Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, UCL Hospitals, Queen Square, London WC1N 3BG, UK.
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George Samandouras
Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, UCL Hospitals, Queen Square, London WC1N 3BG, UK.
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Matt Parton
Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK.
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Janice L. Holton
Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK.
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Anne Weston
The Francis Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK.
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Lucy Collinson
The Francis Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK.
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J. Paul Taylor
Department of Cell & Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105–3678, USA.
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Giampietro Schiavo
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.
View all articles by this author
Michael G. Hanna†
Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK.
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Richard J. Barohn†
Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
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Mazen M. Dimachkie†,‡ [email protected]
Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA.
View all articles by this author
Linda Greensmith†,‡ [email protected]
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.
View all articles by this author

Notes

*
These authors contributed equally to this work.
†
Co-senior authors.
‡Corresponding author. E-mail: [email protected] (L.G.); [email protected] (M.M.D.)

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    Longitudinal observational study investigating outcome measures for clinical trials in inclusion body myositis, Journal of Neurology, Neurosurgery & Psychiatry, 92, 8, (854-862), (2021).https://doi.org/10.1136/jnnp-2020-325141
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    • Andrew R. Findlay,
    • Robert C. Bucelli,
    Immune and Inflammatory Myopathies, Neuroimmunology, (321-345), (2021).https://doi.org/10.1007/978-3-030-61883-4
    Crossref
    • Leonore Unger,
    Therapieoptionen und outcome bei idiopathischen entzündlichen Muskelerkrankungen, Aktuelle Rheumatologie, 46, 04, (388-399), (2021).https://doi.org/10.1055/a-1423-7579
    Crossref
    • A. M. Snedden,
    • J. B. Lilleker,
    • H. Chinoy,
    In Pursuit of an Effective Treatment: the Past, Present and Future of Clinical Trials in Inclusion Body Myositis, Current Treatment Options in Rheumatology, 7, 1, (63-81), (2021).https://doi.org/10.1007/s40674-020-00169-4
    Crossref
    • Heřman Mann,
    • Jiří Vencovský,
    Clinical Trials in Myositis: Where Do We Stand?, Current Treatment Options in Rheumatology, 7, 3, (222-242), (2021).https://doi.org/10.1007/s40674-021-00180-3
    Crossref
    • Hana M. Odeh,
    • Charlotte M. Fare,
    • James Shorter,
    Nuclear-Import Receptors Counter Deleterious Phase Transitions in Neurodegenerative Disease, Journal of Molecular Biology, (167220), (2021).https://doi.org/10.1016/j.jmb.2021.167220
    Crossref
    • Thomas Kirkegaard,
    • James Gray,
    • David A. Priestman,
    • Kerri-Lee Wallom,
    • Jennifer Atkins,
    • Ole Dines Olsen,
    • Alexander Klein,
    • Svetlana Drndarski,
    • Nikolaj H. T. Petersen,
    • Linda Ingemann,
    • David A. Smith,
    • Lauren Morris,
    • Claus Bornæs,
    • Signe Humle Jørgensen,
    • Ian Williams,
    • Anders Hinsby,
    • Christoph Arenz,
    • David Begley,
    • Marja Jäättelä,
    • Frances M. Platt,
    Heat shock protein–based therapy as a potential candidate for treating the sphingolipidoses, Science Translational Medicine, 8, 355, (355ra118-355ra118), (2021)./doi/10.1126/scitranslmed.aad9823
    Abstract
    • Eun-Joo Lee,
    • Ronald L. Neppl,
    Influence of Age on Skeletal Muscle Hypertrophy and Atrophy Signaling: Established Paradigms and Unexpected Links, Genes, 12, 5, (688), (2021).https://doi.org/10.3390/genes12050688
    Crossref
    • Adela Della Marina,
    • Marc Pawlitzki,
    • Tobias Ruck,
    • Andreas van Baalen,
    • Nadine Vogt,
    • Bernd Schweiger,
    • Swantje Hertel,
    • Heike Kölbel,
    • Heinz Wiendl,
    • Corinna Preuße,
    • Andreas Roos,
    • Ulrike Schara-Schmidt,
    Clinical Course, Myopathology and Challenge of Therapeutic Intervention in Pediatric Patients with Autoimmune-Mediated Necrotizing Myopathy, Children, 8, 9, (721), (2021).https://doi.org/10.3390/children8090721
    Crossref
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