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EP39933
Poster Title: Quantitative systems pharmacology model for neurofilament L dynamics in multiple sclerosis and under immunomodulatory therapies
Submitted on 21 Feb 2023
Author(s): Polina Pchelintseva, Anna Mishina, Tatiana Karelina
Affiliations: InSysBio
This poster was presented at ACoP13
Poster Views: 167
Submitted on 21 Feb 2023
Author(s): Polina Pchelintseva, Anna Mishina, Tatiana Karelina
Affiliations: InSysBio
This poster was presented at ACoP13
Poster Views: 167
Abstract: Background: Multiple Sclerosis (MS) is a chronic inflammatory disease of the Central Nervous System (CNS) leading to demyelination and diffuse neurodegeneration in both brain and spinal cord grey and white matter. A major determinant of permanent neurological impairment during MS is axonal degeneration, that results in MS lesions and brain atrophy. One of commonly used biomarkers of axonal degeneration is neurofilament light protein, it is elevated in cerebrospinal fluid and plasma in MS patients [1].
Objectives: To create QSP model that describes neurofilament light dynamics and neurodegeneration processes in MS progression and to apply it for estimation of lymphocyte targeting therapy effect on cytoskeleton breakdown and its CSF markers.
Methods: We suggest ODE model, which includes key cellular processes such as apoptosis, proliferation, migration, and, most importantly, B-T cells interaction with subsequent T-cell activation, based on the following finding that self-reactive brain-homing effector-memory (EM) CD4+ T cells are proliferated upon interaction with memory B cells[2]. The model describes effects of proinflammatory cytokines, expressed by activated lymphocytes on neuronal cytoskeletal dynamics, synthesis of neurofilaments and their degradation, phosphorylation, formation of pathological aggregates, and the release of neurofilament proteins from degenerating axons into the extracellular space with distribution to the CSF. To calibrate the model, we used literature data on the concentration of neurofilaments in brain, cerebrospinal fluid and plasma, the level of phosphorylation, in vitro data on degradation of neurofilaments in different conditions, data containing cell numbers of needed lymphocyte subtypes in blood and CSF in HD and MS patients and cell proliferation assay.
Results: The current QSP model of MS describes the difference between CNS T-cell accumulation in healthy and MS subjects. It recapitulates the major effects on lymphocyte pools in blood and brain observed in clinical trials of natalizumab and rituximab. The model correctly describes the increase of the Nfl concentration in cerebrospinal fluid and plasma, brain and T2 lesions volume change due to MS progression. It describes natalizumab, rituximab, alemtuzumab and sphingolimod treatment effects. Thus natalizumab trratment leads to reduction of Nfl in CSF by 35%. Model also captures the dynamics of recovery of Nfl after treatment discontinuation [3].
Conclusions: The model describes major contributors to MS progression and could serve as the groundwork for more detailed and comprehensive MS models with capabilities relevant to current drug research and development.
Summary: The model describes major contributors to MS progression and could serve as the groundwork for more detailed and comprehensive MS models with capabilities relevant to current drug research and development.References: [1] Martin, S-J et al. Journal of neurology, neurosurgery, and psychiatry vol. 90,9 (2019): 1059-1067.
[2] Jelcic, I. et al. Cell 175, 85-100.e23 (2018).
[3] Proschmann, U. et al. Frontiers in immunology vol. 12 715195. 26 Aug. (2021).
ACoP13 (2022) QSP-462 [www.go-acop.org/?abstract=462]
Objectives: To create QSP model that describes neurofilament light dynamics and neurodegeneration processes in MS progression and to apply it for estimation of lymphocyte targeting therapy effect on cytoskeleton breakdown and its CSF markers.
Methods: We suggest ODE model, which includes key cellular processes such as apoptosis, proliferation, migration, and, most importantly, B-T cells interaction with subsequent T-cell activation, based on the following finding that self-reactive brain-homing effector-memory (EM) CD4+ T cells are proliferated upon interaction with memory B cells[2]. The model describes effects of proinflammatory cytokines, expressed by activated lymphocytes on neuronal cytoskeletal dynamics, synthesis of neurofilaments and their degradation, phosphorylation, formation of pathological aggregates, and the release of neurofilament proteins from degenerating axons into the extracellular space with distribution to the CSF. To calibrate the model, we used literature data on the concentration of neurofilaments in brain, cerebrospinal fluid and plasma, the level of phosphorylation, in vitro data on degradation of neurofilaments in different conditions, data containing cell numbers of needed lymphocyte subtypes in blood and CSF in HD and MS patients and cell proliferation assay.
Results: The current QSP model of MS describes the difference between CNS T-cell accumulation in healthy and MS subjects. It recapitulates the major effects on lymphocyte pools in blood and brain observed in clinical trials of natalizumab and rituximab. The model correctly describes the increase of the Nfl concentration in cerebrospinal fluid and plasma, brain and T2 lesions volume change due to MS progression. It describes natalizumab, rituximab, alemtuzumab and sphingolimod treatment effects. Thus natalizumab trratment leads to reduction of Nfl in CSF by 35%. Model also captures the dynamics of recovery of Nfl after treatment discontinuation [3].
Conclusions: The model describes major contributors to MS progression and could serve as the groundwork for more detailed and comprehensive MS models with capabilities relevant to current drug research and development.
Summary: The model describes major contributors to MS progression and could serve as the groundwork for more detailed and comprehensive MS models with capabilities relevant to current drug research and development.References: [1] Martin, S-J et al. Journal of neurology, neurosurgery, and psychiatry vol. 90,9 (2019): 1059-1067.
[2] Jelcic, I. et al. Cell 175, 85-100.e23 (2018).
[3] Proschmann, U. et al. Frontiers in immunology vol. 12 715195. 26 Aug. (2021).
ACoP13 (2022) QSP-462 [www.go-acop.org/?abstract=462]
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