(S-063) A Translational Quantitative Systems Pharmacology Framework For Alpha-Synuclein-Targeted Parkinson’s Therapies Integrating Pharmacokinetics, Neuronal Biophysics, And Pathological Network Oscillations
Associate Director, QSP Bristol Myers Squibb, United States
Disclosure(s):
Jason Sherfey: No financial relationships to disclose
Objectives: Alpha-synuclein accumulation in substantia nigra pars compacta (SNc) neurons underlies dopaminergic neurodegeneration and associated motor deficits in Parkinson’s disease. Therapeutic development targeting alpha-synuclein is hindered by limited translation of preclinical findings to clinical efficacy. To bridge this gap, we developed a translational Quantitative Systems Pharmacology (QSP) model integrating a published human physiologically-based pharmacokinetic (PBPK) model with a detailed biophysical neuron model of SNc dopaminergic cells and a striatal network generating beta oscillations.
Methods: The PBPK model incorporates transferrin-mediated brain shuttle mechanisms to simulate realistic blood-brain barrier (BBB) permeability, informing predictions of CNS-targeted therapeutic exposure. The SNc neuron model incorporates alpha-synuclein pathology, reactive oxygen species (ROS) dynamics, dopamine turnover and transmission, and electrophysiological spiking activity, calibrated against in vitro data linking alpha-synuclein levels to changes in neuron conductance and firing rates. Downstream, striatal medium spiny neuron networks translate SNc dysfunction into beta-frequency oscillations, a biomarker clinically correlated with motor impairment.
Results: We demonstrate the utility of this integrated QSP framework through example applications, including: (1) Predicting theoretical dose-response relationships for generic antibodies that modulate alpha-synuclein levels delivered via transferrin shuttle platforms. (2) Characterizing mechanistic biomarkers (e.g., alpha-synuclein and beta oscillation modulation) predictive of clinical outcomes and motor symptom alleviation. (3) Exploring the dynamic interplay between molecular pathology (alpha-synuclein), neuronal function (dopamine signaling and ROS), and clinical phenotypes (beta oscillations) by simulating neurodegeneration progression.
Conclusions: This translational modeling approach represents progress toward a robust quantitative pharmacology framework to facilitate rational development and clinical translation of alpha-synuclein-targeted therapies for Parkinson’s disease.
Citations: [1] Chang, Hsueh-Yuan, et al. "Towards a translational physiologically-based pharmacokinetic (PBPK) model for receptor-mediated transcytosis of anti-transferrin receptor monoclonal antibodies in the central nervous system." Journal of Pharmacokinetics and Pharmacodynamics 49.3 (2022): 337-362. [2] Muddapu, V. R., & Chakravarthy, V. S. "Influence of energy deficiency on the subcellular processes of Substantia Nigra Pars Compacta cell for understanding Parkinsonian neurodegeneration." Scientific reports 11.1 (2021): 1754. [3] McCarthy, M. M., et al. "Striatal origin of the pathologic beta oscillations in Parkinson's disease." Proceedings of the national academy of sciences 108.28 (2011): 11620-11625.
