| Author: | Yang, Xiayin |
| Title: | Identifying therapeutic targets and strategies in neuromyelitis optica spectrum disorders associated optic neuritis through temporal window and pathological events |
| Advisors: | Tan, Shaoying (SO) Chan, Henry Ho-lung (SO) |
| Degree: | Ph.D. |
| Year: | 2026 |
| Department: | School of Optometry |
| Pages: | 208 pages : color illustrations |
| Language: | English |
| Abstract: | Background: Neuromyelitis Optica Spectrum Disorder associated with Optic Neuritis (NMOSD-ON) is a devastating autoimmune disorder of the central nervous system that often leads to permanent vision loss. While the disease pathogenesis is known to originate from the binding of pathogenic aquaporin 4-antibodies (AQP4-IgG) to aquaporin 4 (AQP4) proteins on astrocyte endfeet, critical knowledge gaps remain in our understanding of this condition. Key unanswered questions include: (1) the optimal therapeutic window for intervention, (2) the development of safer treatment alternatives to current steroid-based therapies, which often cause significant side effects, and (3) the molecular mechanisms underlying potential therapeutic approaches. Objectives: We first analyzed disease progression by examining the temporal window of phenotypic development in patients. Using this time window, we observed pathological progression in an animal model. Based on the key pathological deterioration within the time window, we explored potential treatment strategies. Finally, we investigated the underlying mechanisms driving disease progression and therapeutic effects. Methods: Optical coherence tomography (OCT) was employed to monitor the peripapillary retinal nerve fiber layer (pRNFL) thickness in patients, comparing with Typical optic neuritis Idiopathic Optic Neuritis (IDON) within different time windows to identify the temporal phenotypic characteristics of NMOSD-ON. Immunofluorescence, Western blot, and functional assessments were utilized to analyze the pathology of the NMOSD-ON animal model and corresponding functional alterations in vivo. The therapeutic effects of Lycium barbarum glycopeptide (LBGP) administration on NMOSD-ON were evaluated, while proteomics was used to investigate the underlying mechanisms. Functional validation of the candidate mediators was subsequently performed. Results: In the first study, our investigations revealed that NMOSD-ON exhibits early pRNFL thinning in the superior and inferior ETDRS sectors within 0-1 month, a previously unreported temporal distinction from IDON. Within the identified critical window of pathological deterioration (≤1 month), the spatiotemporal progression and sequential phenotypes of each pathological event using our novel animal model were systemically evaluated. A sequential pathology: AQP4-IgG binding and astrocyte disintegration peaked within the first week, followed by secondary demyelination and RGC degeneration at 3-4 weeks was observed, confirming demyelination as a downstream event following the astrocytes damage. In the third study, LBGP treatment demonstrated efficacy in reversing NMOSD-induced optic nerve damage. A subsequent mechanistic study revealed that this neuroprotective effect was mediated through LBGP's selective targeting of Cathepsin Z dependent neuroinflammatory pathways. Conclusion: Our research began by characterizing NMOSD-ON phenotypes to define the critical time windows for disease onset and progression. Leveraging these temporal insights, we established a novel NMOSD-ON animal model to systematically recapitulate key pathological events. This model subsequently enabled us to investigate both the therapeutic efficacy of LBGP intervention and its underlying mechanisms of action. |
| Rights: | All rights reserved |
| Access: | open access |
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