Objective: Glunomab, a monoclonal antibody designed to inhibit the interaction between tissue plasminogen activator (tPA) and the N-methyl-D-aspartate receptor (NMDAr), has demonstrated therapeutic potential across multiple neurological disease models. tPA plays a key role in brain function in both health and disease, with growing evidence implicating it in Parkinson’s disease (PD) pathophysiology. In this study, we evaluated the effects of repeated intravenous administrations of glunomab, initiated at different disease stages to simulate delayed treatment initiation in clinical settings, on neuroinflammation and neurodegeneration in a human α-synuclein (hα-syn) mouse model of PD.

Background: We previously identified a population of tPA-expressing GABAergic striatal neurons projecting to dopaminergic neurons in the substantia nigra (SN) and observed elevated tPA levels in the SN of an hα-syn mouse model. In this model, both genetic tPA deficiency and repeated intravenous administrations of glunomab at an early disease stage protected dopaminergic neurons from hα-syn-induced degeneration. These initial findings highlighted the role of the tPA-NMDAr pathway in PD pathology and its potential as a novel therapeutic strategy to slow disease progression.

Method: Male and female wild-type mice received unilateral adeno-associated virus expressing hα-syn (AAV-hα-syn) or an empty vector in the SN. Glunomab was administered weekly starting at different time points post-injection. After four weeks, motor function was assessed using the corridor task, and immunohistochemistry evaluated dopaminergic neurodegeneration, immune cell activation, blood-brain barrier permeability, and neuroinflammatory markers.

Results: Glunomab provided neuroprotection against α-syn-induced degeneration, even when treatment was initiated at late disease stages. This was associated with reduced immune cell infiltration in the SN, decreased microglia activation, lower plasma NFL levels, and improved sensorimotor function.

Conclusion: tPA is a key driver of α-syn-induced neuroinflammation and neurodegeneration in PD. Glunomab effectively suppresses tPA-mediated neuroinflammation, prevents neurodegeneration, and improves motor function. A humanized version, LYS241, is undergoing IND/CTA-enabling studies in preparation for future clinical trials.

References: Torrente, D., Su, E.J., Citalán-Madrid, A.F. et al. The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity. J Neuroinflammation 22, 8 (2025). https://doi.org/10.1186/s12974-025-03336-3

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-therapeutic-targeting-the-tpa-nmdar-interaction-for-parkinsons-disease/