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Investigating the effects of pharmacological upregulation of the heat shock response in models of inclusion body myositis

Spicer, Charlotte Jayne; (2018) Investigating the effects of pharmacological upregulation of the heat shock response in models of inclusion body myositis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Inclusion body myositis (IBM) is the most common acquired muscle disease affecting adults over the age of 50 and is characterised by a combination of inflammatory and degenerative features. Although the precise cause of IBM is unknown, previous therapeutic trials have targeted only the inflammatory component of IBM, but all have been unsuccessful and as a result, IBM remains untreatable. The characteristic degenerative features of IBM include the accumulation and aggregation of a number of proteins, most likely as a result of disturbances in protein homeostasis. It is therefore possible that targeting protein mishandling may be an effective therapeutic strategy for IBM. Indeed, recent results from our laboratory have demonstrated that upregulation of the cytoprotective heat shock response (HSR) with Arimoclomol, a novel co-inducer of the HSR, ameliorates IBM-like pathology in cultured primary rat muscle cells, by improving protein handling. In this study, these results were taken forward into an in vivo pre-clinical trial, using a transgenic mouse model of multisystem proteinopathy (MSP), caused by a mutation in the valosin-containing protein (VCP) gene. This model recapitulates many key features of IBM in muscle. Treatment with Arimoclomol was found to significantly attenuate IBM-like characteristics in the muscle of 14-month old mutant VCP mice and importantly, also improved muscle strength. To establish whether these pathological findings are reproduced in a more clinically relevant, human model of IBM, dermal fibroblasts were obtained from sporadic IBM patients or MSP patients expressing mutant VCP, presenting with an inclusion body myopathy. These fibroblasts recapitulated the IBM disease phenotype, which was ameliorated following treatment with Arimoclomol. The results presented in this Thesis show that Arimoclomol reduces characteristic pathological features of IBM both in vivo, in a mutant VCP mouse model and in vitro, in patient-derived dermal fibroblasts. These findings build upon our previous in vitro data and together provide strong evidence to suggest that Arimoclomol may be a potential therapeutic agent for the treatment of IBM.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigating the effects of pharmacological upregulation of the heat shock response in models of inclusion body myositis
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10052418
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