Objective: Understanding the biological link between alpha-synuclein biomarker changes and clinical outcome using computer simulation.
Background: A number of disease modifying therapeutic interventions focused on reducing oligomerization of alpha-synuclein are making their way through clinical development. All these trials include patients on various formulations of dopaminergic standard-of-care. In the absence of any validated biomarker of neurodegeneration, the challenge is to demonstrate clinical efficacy.
Method: We used a previously published and well calibrated Quantitative Systems Pharmacology model of the humanized basal ganglia motor circuit. In this computational neuroscience model, the calculated beta/gamma ratio of local field potential power in the subthalamic nucleus is strongly correlated with bradykinesia and rigidity. We implemented systematically the following documented effects of oligomeric alpha-synuclein on voltage- and ligand gated ion channels, such as (1) ATP dependent K+ channel, (2) SK conductance, (3) Ca-overload, (4) various levels of Glutamate overload and extrasynaptic NMDA-R hyperactivation and (5) hyperactivity of locus coeruleus (LC). We determined the relative contribution of these processes on the time-OFF, a validated in silico biomarker.
Results: Glutamate, NMDA-R activation and LC hyperactivity contribute each in an unique way to the changes in beta/gamma ratio. Using the clinically calibrated QSP model we can derive a relationship between alpha-synuclein levels and clinical outcome. Sensitivity analysis helps to identify key pathways with potential therapeutic impact to reduce or reverse the clinical effects of alpha-synuclein pathology. Different formulations of standard-of-care (SoC) dopaminergic therapy affect these pathways in a unique way.
Conclusion: This mechanism-based biosimulation model could support clinical trial design of augmentation therapy with disease-modifying interventions in Parkinson’s Disease by assessing the pharmacodynamic interaction of dopaminergic SoC therapy with the alpha-synuclein pathways.
To cite this abstract in AMA style:
H. Geerts, S. Short. The Effect of Modulating Alpha-synuclein Aggregation on Clinical Outcome in the Presence of Standard-of-care Dopaminergic Therapy in Parkinson’s Disease. A Quantitative Systems Pharmacology Approach. [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/the-effect-of-modulating-alpha-synuclein-aggregation-on-clinical-outcome-in-the-presence-of-standard-of-care-dopaminergic-therapy-in-parkinsons-disease-a-quantitative-systems-pharmacology-ap/. Accessed July 1, 2025.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-effect-of-modulating-alpha-synuclein-aggregation-on-clinical-outcome-in-the-presence-of-standard-of-care-dopaminergic-therapy-in-parkinsons-disease-a-quantitative-systems-pharmacology-ap/