Thomas-Black, Gilbert Joe;
(2022)
Novel Biomarkers and Therapeutics in Friedreich's Ataxia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Friedreich’s ataxia (FRDA) is a devastating, inherited neurodegenerative disorder that can manifest from early childhood through to old age. There have been many therapeutic trials of possible disease-modifying agents in FRDA and these have often been hampered by a lack of sensitive measures to track disease progression. FRDA is clinically heterogeneous and current clinical rating scales lack sensitivity, particularly over the relatively short time periods of clinical trials. Multiple imaging and blood biomarkers have so far been proposed, but few have been assessed longitudinally and therefore their utility remains unknown. Novel response biomarkers able to objectively measure disease progression in FRDA could thus enhance the evaluation of therapeutic interventions. The majority of this thesis is dedicated to describing a multi-modal approach to the evaluation of potential imaging and biofluid biomarkers for FRDA in large cohorts of patients over time scales relevant to clinical trial design. After outlining the relevant genetic, pathophysiological and clinical features of FRDA, the current state of therapeutic and biomarker research in FRDA is then reviewed. Several approaches to, and outcomes from, biomarker evaluation are described, including digital ELISA-based immunoassay of neuron- and glial-derived proteins, optical coherence tomography and advanced MRI of the spinal cord. The serendipitous finding of improved neuromuscular function in a severely affected individual with FRDA whilst at high altitude lead to the second part of this thesis, an investigation into potential mechanisms for this improvement. Studies in cell models, animals and human subjects using molecular biological techniques are described and their implication for the use of hypoxia as a novel therapy in FRDA elaborated upon. The two parts of this thesis are therefore linked in that improved response biomarkers could ultimately prove useful in a future trial of therapeutic hypoxia.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Novel Biomarkers and Therapeutics in Friedreich's Ataxia |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | 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 > Clinical and Movement Neurosciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10148667 |
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