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Title: Development of new therapeutic strategies for sporadic Inclusion Body Myositis
Author: Miller, A. D.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Abstract:
Sporadic inclusion body myositis (IBM) is the commonest myopathy acquired after 50 years of age and causes significant disability. No effective treatment exists despite several clinical trials of immunotherapies. This reflects a lack of pre-clinical disease models. The work described in this thesis began with development of such a system, in which disease relevant pathological outcome measures were characterised in vitro using primary satellite cell cultures. Through over-expression of β-Amyloid Precursor Protein or exposure to inflammatory mediators IL1β and TNFα, IBM-like pathology was induced. Myotubes demonstrated ubiquinated intracellular aggregates, increased expression of MHC Class I, cytoplasmic translocation of TDP-43, ER stress, calcium dyshomeostasis and activation of NFκB. As some of these are proposed to be central pathogenic mechanisms in IBM, they provide a panel of tools on which to assess new IBM treatment strategies. The effects of heat shock response augmentation were examined using Arimoclomol, a co-inducer of the transcription factor HSF-1 that drives expression of key endogenous Heat Shock Proteins. Arimoclomol treatment ameliorated several IBM-relevant features, represented by improved cell viability, reduced ER stress, inhibition of NFκB and reduced cytoplasmic translocation of TDP-43. These data supported further evaluation of HSR manipulation as a potential therapy for IBM. Therefore, Arimoclomol was advanced into a randomised, placebo-controlled clinical trial involving 24 patients with IBM over one year. The primary outcome measure was safety and tolerability. Muscle biopsy was performed before and after the treatment phase to evaluate HSP expression and histopathological changes. Together, this in vitro model and clinical trial represent a novel translational research pathway in IBM, the lack of which has hampered the development of effective treatments for this disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.668476  DOI: Not available
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