Rapamycin for inclusion body myositis: targeting non ...



Rapamycin for inclusion body myositis: targeting non-inflammatory mechanismsJames B Lilleker1,2, Marwan Bukhari3, Hector Chinoy4,5Affiliations:Centre for Musculoskeletal Research, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKGreater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UKUniversity Hospitals of Morecambe bay NHS Foundation Trust, Royal Lancaster Infirmary, Ashton Road, Lancaster, UKRheumatology Department, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Stott Lane, Salford, UKNIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UKInclusion body myositis (IBM) is an acquired myopathy usually occurring in those aged over 50 years and with a prevalence of 33 cases per million. Whilst conventionally grouped with the idiopathic inflammatory myopathies, IBM has several unique clinical and pathological characteristics. Despite muscle inflammation being a prominent feature, the disease is resistant to treatment with routine immunosuppressive therapies, none of which have demonstrated sustained therapeutic benefits. Disease progression is characterised by an accumulation of degenerative change in skeletal muscle, including misfolded protein aggregates and rimmed vacuoles. The exact sequence of events that culminate in severely disabling muscle atrophy is the subject of intense debate and the lack of effective treatment represents a significant unmet need for sufferers.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s00401-015-1384-5", "ISSN" : "0001-6322", "PMID" : "25579751", "abstract" : "Sporadic inclusion body myositis (sIBM) is the most frequently acquired myopathy in patients over 50 years of age. It is imperative that neurologists and rheumatologists recognize this disorder which may, through clinical and pathological similarities, mimic other myopathies, especially polymyositis. Whereas polymyositis responds to immunosuppressant drug therapy, sIBM responds poorly, if at all. Controversy reigns as to whether sIBM is primarily an inflammatory or a degenerative myopathy, the distinction being vitally important in terms of directing research for effective specific therapies. We review here the pros and the cons for the respective hypotheses. A possible scenario, which our experience leads us to favour, is that sIBM may start with inflammation within muscle. The rush of leukocytes attracted by chemokines and cytokines may induce fibre injury and HLA-I overexpression. If the protein degradation systems are overloaded (possibly due to genetic predisposition, particular HLA-I subtypes or ageing), amyloid and other protein deposits may appear within muscle fibres, reinforcing the myopathic process in a vicious circle.", "author" : [ { "dropping-particle" : "", "family" : "Benveniste", "given" : "Olivier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stenzel", "given" : "Werner", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hilton-Jones", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sandri", "given" : "Marco", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boyer", "given" : "Olivier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Engelen", "given" : "Baziel G M", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" } ], "container-title" : "Acta Neuropathologica", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "5", "13" ] ] }, "page" : "611-624", "title" : "Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: the inflammatory egg comes before the degenerative chicken", "type" : "article-journal", "volume" : "129" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[1]", "plainTextFormattedCitation" : "[1]", "previouslyFormattedCitation" : "[1]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[1]There has been a shift away from targeting immunosuppressive and immunomodulatory pathways and towards alternative damage-inducing mechanisms. Encouraging signals have been demonstrated in several small-scale studies, although a robust demonstration of long-term effects modifying the relentless accumulation of disability has not yet been forthcoming. For example, despite promising pilot work ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1212/WNL.0000000000001070", "ISBN" : "0000000000", "ISSN" : "0028-3878", "PMID" : "25381300", "abstract" : "OBJECTIVE: To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial. METHODS: We measured transforming growth factor \u03b2 signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase. RESULTS: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied (p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions. CONCLUSIONS: Transforming growth factor \u03b2 superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks.", "author" : [ { "dropping-particle" : "", "family" : "Amato", "given" : "Anthony a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sivakumar", "given" : "Kumaraswamy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goyal", "given" : "Namita", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "David", "given" : "William S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salajegheh", "given" : "Mohammad", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Praestgaard", "given" : "Jens", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lach-Trifilieff", "given" : "Estelle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trendelenburg", "given" : "A.-U.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laurent", "given" : "Didier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Glass", "given" : "David J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roubenoff", "given" : "Ronenn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tseng", "given" : "Brian S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Greenberg", "given" : "Steven a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurology", "id" : "ITEM-1", "issue" : "24", "issued" : { "date-parts" : [ [ "2014", "12", "9" ] ] }, "page" : "2239-2246", "title" : "Treatment of sporadic inclusion body myositis with bimagrumab", "type" : "article-journal", "volume" : "83" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[2]", "plainTextFormattedCitation" : "[2]", "previouslyFormattedCitation" : "[2]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[2], a recently completed large phase 2b/3 multicentre study of the activin receptor inhibitor Bimagrumab did not meet its primary endpoint (change in six minute walking distance [6MWD]) ( Identifier: NCT01925209). It is postulated that meaningful differences between the groups were not detected due to the primary outcome measure chosen being insensitive to the disability observed in patients with IBM, rather than because of a failure of the treatment per se. In order to avoid similar failures, highly sensitive surrogate outcome measures such as the rate of accumulation of fatty change on muscle magnetic resonance imaging (MRI), are likely to be increasingly used in future clinical trials.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S1474-4422(15)00242-2", "ISSN" : "14744422", "author" : [ { "dropping-particle" : "", "family" : "Morrow", "given" : "Jasper M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sinclair", "given" : "Christopher D J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fischmann", "given" : "Arne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Machado", "given" : "Pedro M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reilly", "given" : "Mary M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yousry", "given" : "Tarek A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thornton", "given" : "John S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hanna", "given" : "Michael G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Lancet Neurology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "1" ] ] }, "note" : "Concept of standardised response mean to described ability of a measure to reflect change.", "page" : "65-77", "title" : "MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[3]", "plainTextFormattedCitation" : "[3]", "previouslyFormattedCitation" : "[3]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[3] Such practice may permit conduct of well-powered clinical trials with fewer participants and over shorter duration although acceptance of such measures by the regulatory authorities is a hurdle not yet overcome. Additionally, if the use of highly targeted therapies is to increase, specific diagnostic criteria for the disease in question are required. Whilst these do exist for IBM, it is noted that such criteria require the demonstration of particular patterns of muscle weakness.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1212/WNL.0000000000000642", "ISSN" : "1526-632X", "PMID" : "24975859", "abstract" : "OBJECTIVE: To use patient data to evaluate and construct diagnostic criteria for inclusion body myositis (IBM), a progressive disease of skeletal muscle. METHODS: The literature was reviewed to identify all previously proposed IBM diagnostic criteria. These criteria were applied through medical records review to 200 patients diagnosed as having IBM and 171 patients diagnosed as having a muscle disease other than IBM by neuromuscular specialists at 2 institutions, and to a validating set of 66 additional patients with IBM from 2 other institutions. Machine learning techniques were used for unbiased construction of diagnostic criteria. RESULTS: Twenty-four previously proposed IBM diagnostic categories were identified. Twelve categories all performed with high (\u226597%) specificity but varied substantially in their sensitivities (11%-84%). The best performing category was European Neuromuscular Centre 2013 probable (sensitivity of 84%). Specialized pathologic features and newly introduced strength criteria (comparative knee extension/hip flexion strength) performed poorly. Unbiased data-directed analysis of 20 features in 371 patients resulted in construction of higher-performing data-derived diagnostic criteria (90% sensitivity and 96% specificity). CONCLUSIONS: Published expert consensus-derived IBM diagnostic categories have uniformly high specificity but wide-ranging sensitivities. High-performing IBM diagnostic category criteria can be developed directly from principled unbiased analysis of patient data. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that published expert consensus-derived IBM diagnostic categories accurately distinguish IBM from other muscle disease with high specificity but wide-ranging sensitivities.", "author" : [ { "dropping-particle" : "", "family" : "Lloyd", "given" : "Thomas E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mammen", "given" : "Andrew L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Amato", "given" : "Anthony a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weiss", "given" : "Michael D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Needham", "given" : "Merrilee", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Greenberg", "given" : "Steven a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurology", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2014", "7", "29" ] ] }, "page" : "426-33", "title" : "Evaluation and construction of diagnostic criteria for inclusion body myositis.", "type" : "article-journal", "volume" : "83" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[4]", "plainTextFormattedCitation" : "[4]", "previouslyFormattedCitation" : "[4]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[4] Assuming the onset of muscle weakness occurs as the final and irreversible consequence of disease, alternative diagnostic tools might be required to facilitate earlier diagnosis and commencement of treatment prior to onset of significant muscle weakness.Two drugs with novel non-inflammatory mechanisms of action are currently being evaluated for the treatment of IBM. The first, Arimoclomol, co-induces the heat shock response by prolonging activation of Heat Shock Factor-1. Heat shock proteins act as chaperone molecules in protein homeostasis by promoting normal protein folding. Upregulation of the heat shock protein pathway has the potential to promote normalisation of protein handling within muscle and prevent ongoing activation of damage-inducing mechanisms in IBM muscle. In a recent double-blind, placebo-controlled phase 2a study, 24 patients with IBM were randomised to Arimoclomol or placebo (2:1 ratio). Safety and promising therapeutic signals were demonstrated and a larger scale phase 2/3 study has recently started recruitment ( Identifier: NCT02753530).ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/scitranslmed.aad4583", "ISSN" : "1946-6234", "author" : [ { "dropping-particle" : "", "family" : "Ahmed", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Machado", "given" : "P. 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L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pasnoor", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gallagher", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Statland", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "C.-H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kalmar", "given" : "B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brady", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sethi", "given" : "H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Samandouras", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parton", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holton", "given" : "J. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weston", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collinson", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "J. P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schiavo", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hanna", "given" : "M. G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barohn", "given" : "R. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dimachkie", "given" : "M. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Greensmith", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science Translational Medicine", "id" : "ITEM-1", "issue" : "331", "issued" : { "date-parts" : [ [ "2016", "3", "23" ] ] }, "page" : "331ra41-331ra41", "title" : "Targeting protein homeostasis in sporadic inclusion body myositis", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[5]", "plainTextFormattedCitation" : "[5]", "previouslyFormattedCitation" : "[5]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[5]The second is Rapamycin (sirolimus), which seeks to restore aberrant autophagic (protein degradation) pathways evident in IBM muscle by inhibiting mTOR, a protein kinase which regulates several intracellular processes including survival, protein synthesis and autophagy. Rapamycin also has immunosuppressive effects mediated via inhibition of interleukin-2 signalling and as such is used to prevent rejection after organ transplant. Variable results have been encountered in pre-clinical work using Rapamycin in IBM mouse models that over-express VCP to induce an IBM-like state.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0122888", "ISSN" : "1932-6203", "PMID" : "25884947", "abstract" : "Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion body myopathy (hIBM) associated with Paget disease of bone (PDB), frontotemporal dementia (FTD), more recently termed multisystem proteinopathy (MSP). Affected individuals exhibit scapular winging and die from progressive muscle weakness, and cardiac and respiratory failure, typically in their 40s to 50s. Histologically, patients show the presence of rimmed vacuoles and TAR DNA-binding protein 43 (TDP-43)-positive large ubiquitinated inclusion bodies in the muscles. We have generated a VCPR155H/+ mouse model which recapitulates the disease phenotype and impaired autophagy typically observed in patients with VCP disease. Autophagy-modifying agents, such as rapamycin and chloroquine, at pharmacological doses have previously shown to alter the autophagic flux. Herein, we report results of administration of rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, and chloroquine, a lysosomal inhibitor which reverses autophagy by accumulating in lysosomes, responsible for blocking autophagy in 20-month old VCPR155H/+ mice. Rapamycin-treated mice demonstrated significant improvement in muscle performance, quadriceps histological analysis, and rescue of ubiquitin, and TDP-43 pathology and defective autophagy as indicated by decreased protein expression levels of LC3-I/II, p62/SQSTM1, optineurin and inhibiting the mTORC1 substrates. Conversely, chloroquine-treated VCPR155H/+ mice revealed progressive muscle weakness, cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-I/II, p62/SQSTM1, and optineurin expression levels. Our in vitro patient myoblasts studies treated with rapamycin demonstrated an overall improvement in the autophagy markers. Targeting the mTOR pathway ameliorates an increasing list of disorders, and these findings suggest that VCP disease and related neurodegenerative multisystem proteinopathies can now be included as disorders that can potentially be ameliorated by rapalogs.", "author" : [ { "dropping-particle" : "", "family" : "Nalbandian", "given" : "Ang\u00e8le", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Llewellyn", "given" : "Katrina J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nguyen", "given" : "Christopher", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yazdi", "given" : "Puya G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kimonis", "given" : "Virginia E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLOS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Komatsu", "given" : "Maasaki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2015", "4", "17" ] ] }, "page" : "e0122888", "title" : "Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1093/hmg/dds524", "ISSN" : "0964-6906", "PMID" : "23250913", "abstract" : "Autophagy is dysfunctional in many degenerative diseases including myopathies. Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone, fronto-temporal dementia and amyotrophic lateral sclerosis (IBMPFD/ALS). VCP is necessary for protein degradation via the proteasome and lysosome. IBMPFD/ALS mutations in VCP disrupt autophagosome and endosome maturation resulting in vacuolation, weakness and muscle atrophy. To understand the regulation of autophagy in VCP-IBM muscle, we examined the AKT/FOXO3 and mammalian target of rapamycin (mTOR) pathways. Basal Akt and FOXO3 phosphorylation was normal. In contrast, the phosphorylation of mTOR targets was decreased. Consistent with this, global protein translation was diminished and autophagosome biogenesis was increased in VCP-IBM muscle. Further mTORC1 inhibition with rapamycin hastened weakness, atrophy and vacuolation in VCP-IBM mice. This was accompanied by the accumulation of autophagic substrates such as p62, LC3II and ubiquitinated proteins. The decrease in mTOR signaling was partially rescued by insulin and to a lesser extent by amino acid (AA) stimulation in VCP-IBM muscle. Cells expressing catalytically inactive VCP or treated with a VCP inhibitor also failed to activate mTOR upon nutrient stimulation. Expression of a constitutively active Rheb enhanced mTOR activity and increased the fiber size in VCP-IBM mouse skeletal muscle. These studies suggest that VCP mutations may disrupt mTOR signaling and contribute to IBMPFD/ALS disease pathogenesis. Treatment of some autophagic disorders with mTOR inhibitors such as rapamycin may worsen disease.", "author" : [ { "dropping-particle" : "", "family" : "Ching", "given" : "J. K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Elizabeth", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ju", "given" : "J.-S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lusk", "given" : "C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pittman", "given" : "S. K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weihl", "given" : "C. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Human Molecular Genetics", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2013", "3", "15" ] ] }, "page" : "1167-1179", "title" : "mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[6,7]", "plainTextFormattedCitation" : "[6,7]", "previouslyFormattedCitation" : "[6,7]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[6,7] Despite this, a recent study presented at American College of Rheumatology 2017 meeting has stimulated further interest of use of this compound for the treatment of IBM.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Benveniste", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hogrel", "given" : "JY", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Annoussamy", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bachasson", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rigolet", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Servais", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salem", "given" : "JE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hervier", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Landon Cardinal", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mariampillai", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hulot", "given" : "JS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carlier", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allenbach", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis Rheumatol.", "id" : "ITEM-1", "issue" : "Suppl 10", "issued" : { "date-parts" : [ [ "2017" ] ] }, "title" : "Rapamycin Vs. Placebo for the Treatment of Inclusion Body Myositis: Improvement of the 6 Min Walking Distance, a Functional Scale, the FVC and Muscle Quantitative MRI [abstract]", "type" : "article-journal", "volume" : "69" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[8]", "plainTextFormattedCitation" : "[8]", "previouslyFormattedCitation" : "[8]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[8]In this prospective, randomised, double blind, placebo-controlled phase 2b trial conducted at Pitié-Salpêtrière University Hospital (Paris, France), 44 patients received oral Rapamycin and 22 received placebo over a 12-month period. Quadriceps strength using quantitative muscle testing was chosen as the primary outcome measure, with 6MWD and various other measures being used as secondary outcomes. Interestingly, whilst no difference in the primary outcome was identified at 12 months (mean relative change: -11.07% vs. -12.36 %), significantly less fatty replacement of muscle in the quadriceps and hamstrings was observed in the actively treated arm. Additionally, those receiving Rapamycin showed less pronounced loss of contractile cross-sectional area in the quadriceps. Quite why these apparent effects did not translate in to a significant measurable difference in quadriceps strength remains uncertain, especially as significant beneficial effects were also observed on 6MWD, the IBM weakness composite index and the forced vital capacity in the actively treated group. An open phase continuation of this study is ongoing to further evaluate these findings.These recent results are encouraging and look to usher in a new dawn of IBM treatments focussing on non-immune mechanisms. This alternative approach reflects the culmination of careful translational research endeavours over several decades. Whilst there are several barriers yet to be overcome, there is hope on the horizon for patients with this severely debilitating condition.ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1 Benveniste O, Stenzel W, Hilton-Jones D, et al. Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: the inflammatory egg comes before the degenerative chicken. Acta Neuropathol 2015;129:611–24. doi:10.1007/s00401-015-1384-52 Amato A a, Sivakumar K, Goyal N, et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology 2014;83:2239–46. doi:10.1212/WNL.00000000000010703 Morrow JM, Sinclair CDJ, Fischmann A, et al. MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study. Lancet Neurol 2016;15:65–77. doi:10.1016/S1474-4422(15)00242-24 Lloyd TE, Mammen AL, Amato A a, et al. Evaluation and construction of diagnostic criteria for inclusion body myositis. Neurology 2014;83:426–33. doi:10.1212/WNL.00000000000006425 Ahmed M, Machado PM, Miller A, et al. Targeting protein homeostasis in sporadic inclusion body myositis. Sci Transl Med 2016;8:331ra41-331ra41. doi:10.1126/scitranslmed.aad45836 Nalbandian A, Llewellyn KJ, Nguyen C, et al. Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy. PLoS One 2015;10:e0122888. doi:10.1371/journal.pone.01228887 Ching JK, Elizabeth S V., Ju J-S, et al. mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum Mol Genet 2013;22:1167–79. doi:10.1093/hmg/dds5248 Benveniste O, Hogrel J, Annoussamy M, et al. Rapamycin Vs. Placebo for the Treatment of Inclusion Body Myositis: Improvement of the 6 Min Walking Distance, a Functional Scale, the FVC and Muscle Quantitative MRI [abstract]. Arthritis Rheumatol 2017;69. ................
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