Soo, Audrey Ker Shin; (2023) Accelerating precision therapy for rare, genetic childhood neurological disorders using a multimodal approach. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Precision medicine has huge potential, particularly for inherited monogenic childhood neurological disorders where there is a real paucity of effective disease-modifying treatments. Despite the precedent set by life-transformative treatments for spinal muscular atrophy, neuronal ceroid lipofuscinosis and aromatic l-amino acid decarboxylase deficiency, significant hurdles remain in the field, related to disease rarity, lack of understanding of the underlying disease and its biological mechanisms, funding difficulties and clinical trial design and execution. The lack of robust biomarkers is a particularly challenging issue, rendering it very difficult to objectively measure disease progression or evaluate the efficacy of a novel therapy. As a result, this can hamper the development of precision therapies. This exact issue is evident for the rare, progressive disorder, PLA2G6-Associated Neurodegeneration (PLAN). With the aim of discovering new biomarkers and accelerating clinical trial readiness for PLAN, I adopted a multimodal approach to identify reliable measures of disease progression that could potentially be utilised as outcome measures in a clinical trial, including (i) a retrospective, international natural history study (ii) development and validation of a disease-specific clinical rating scale (iii) prospective, longitudinal quantitative neuroimaging and (iv) biomarker discovery through proteomics analysis. The natural history study provided key data that allowed delineation of disease progression in PLAN, including Kaplan-Meier plots for survival and time to loss of ambulation. A new disease-specific clinical rating scale [Childhood-onset PLAN Disease Rating Scale (CoPLAN DRS)] was developed and validated in a cohort of patients with promising utility and reliability. Brain iron in the globus pallidus was systematically quantified through Quantitative Susceptibility Mapping (QSM) for the first time in this cohort showing very strong, positive correlation between QSM values and age, a surrogate for disease progression. Biomarker discovery through proteomics led to the identification of several potential biomarkers from PLAN patients’ dried blood spots, including a novel biomarker, nicastrin. Neurodegenerative biomarkers in plasma were significantly elevated in patients when compared to controls, including tau and neurofilament light (NfL). There was a strong, negative correlation between NfL and disease progression, a unique longitudinal pattern that has not been seen in other neurodegenerative disorders. Overall, this multimodal toolkit will be of use in future precision medicine clinical trials for PLAN.

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