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Title: Development of biofluid biomarkers for Huntington's disease
Author: Byrne, Lauren Mary
ISNI:       0000 0004 9346 7207
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Though no treatments can currently prevent onset or slow progression of Huntington’s disease (HD), many huntingtin-lowering drug candidates targeting the root cause of HD are in the development pipeline. This brings much hope that disease-modifying treatments for HD will be a reality. However, success of potential candidates may be hindered by a lack of sensitive tools to measure biological efficacy over short intervals. Decades of attempts to develop robust biofluid biomarkers of HD progression has yielded little success or replication of results. Cerebrospinal fluid (CSF), fluid that bathes the brain and is enriched for brain-specific proteins, is a plausible target for uncovering neuropathologically relevant markers of HD. However, a lack of standardisation of collection protocols, biological rationale and technological sensitivity has hampered the progress of CSF biomarkers within the field of HD. At the core of this thesis lies the HD-CSF study – a single-site CSF collection study, with a standardised protocol designed to generate high-quality CSF and blood with matched clinical and phenotypic data. It is the first CSF collection prospectively designed for longitudinal sampling and having matching MRI data. Mutant huntingtin protein (mHTT) can be quantified in CSF and has been identified as having high potential as a biomarker of HD progression. Further, the interpretation of drug-induced lowering of mHTT in the CNS relies upon elucidation of the natural history of CSF mHTT in HD gene carriers. Neurofilament light (NfL) has emerged as a promising marker of neuronal damage that can be measured in CSF and blood. This thesis includes the first reports of blood NfL in HD, head to head comparison of NfL and mHTT, and assessment of longitudinal alterations in mHTT and NfL, in addition to proposed biomarkers of specific pathogenic pathways. The work in this thesis will have significant implications for the use of NfL and mHTT as pharmacodynamic markers of HD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available