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dc.contributor.advisorCarragher, Neil
dc.contributor.advisorChandran, Siddharthan
dc.contributor.authorTelford-Cooke, Leolie Lucy
dc.date.accessioned2022-06-22T10:40:31Z
dc.date.available2022-06-22T10:40:31Z
dc.date.issued2022-06-17
dc.identifier.urihttps://hdl.handle.net/1842/39170
dc.identifier.urihttp://dx.doi.org/10.7488/era/2421
dc.description.abstractMultiple Sclerosis (MS) is described as a neurodegenerative autoimmune condition causing increased disability with age. The current disease modifying therapies (DMTs), which are approved for the treatment of MS by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), are all immunomodulatory; these small molecules and monoclonal antibodies target the immune system to ameliorate the symptoms of MS. None of these therapies have the ability to halt or reverse the symptoms. In MS, immune cells are known to be autoreactive to oligodendrocytes, thus destroying the protective myelin sheath, demyelinating axons and causing neurodegeneration. Oligodendrocyte progenitor cells (OPCs) are known to differentiate into mature myelinating oligodendrocytes to naturally remyelinate demyelinated axons and this biological process can be targeted by small molecules with the hypothesis that increasing the number of mature myelinating oligodendrocytes will increase remyelination to stop the progression of, and potentially reverse, the symptoms of MS. As such, this research used high-throughput drug screening to test multiple small molecule libraries on in vitro human induced pluripotent stem cell (iPSC)-derived OPCs to identify novel compounds that promote OPC differentiation, quantified by immunocytochemistry staining for the mature oligodendrocyte protein myelin basic protein (MBP). Subsequent analysis of potential mechanisms of action (MoAs) of the hit compounds was performed using in silico techniques such as network and pathway analysis. In addition, one novel compound, SGC-CBP30, which was identified during screening, was investigated in an in vivo experimental autoimmune encephalomyelitis (EAE) model of MS in mice to show the compound’s functional remyelination capacity and reduction of MS symptoms. In total ten compounds were identified as hits that increased the differentiation of OPCs, of which five were novel structures not previously implicated in OPC differentiation and one, latanoprost, was a novel drug class that has not previously been reported in the literature within the context of MS. From the MoA profiling analysis of these compounds, eight proteins were identified as potential novel targets for promoting OPC differentiation. EP300, the target for SGC-CBP30, was also identified to be a crucial protein in several pathways associated with the other hit compound MoAs. SGC-CBP30 was found to have action in vivo via an alternative mechanism to another compound which also targets EP300 (anacardic acid); this may be due to anacardic acid’s reduced selectivity to EP300. This research has therefore been able to identify novel small molecules that promote OPC differentiation, as well as highlighting potential MoA targets for these compounds, including inhibiting EP300 with an epigenetic modulator. This research thus provides potential drug repurposing candidates for clinical trials and therapeutic targets for novel MS drug discovery and adds to the knowledge of how the compounds interact with potential protein targets and biological pathways to increase OPC differentiation and the remyelination axons.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.titleDevelopment of phenotypic approaches to advance drug discovery and development for multiple sclerosisen
dc.title.alternativeThe development of phenotypic approaches to advance drug discovery and development for multiple sclerosisen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2023-06-17en
dcterms.accessRightsRestricted Accessen


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