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Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF

In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to the propagation of pathology and neuronal toxicity. These species,...

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Autores principales: Audrain, Mickael, Egesipe, Anne-Laure, Tentillier, Noémie, Font, Laure, Ratnam, Monisha, Mottier, Lorene, Clavel, Mathieu, Le Roux-Bourdieu, Morgan, Fenyi, Alexis, Ollier, Romain, Chevalier, Elodie, Guilhot, Florence, Fuchs, Aline, Piorkowska, Kasia, Carlyle, Becky, Arnold, Steven E, Berry, James D, Luthi-Carter, Ruth, Adolfsson, Oskar, Pfeifer, Andrea, Kosco-Vilbois, Marie, Seredenina, Tamara, Afroz, Tariq
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10644982/
https://www.ncbi.nlm.nih.gov/pubmed/38025276
http://dx.doi.org/10.1093/braincomms/fcad306
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author Audrain, Mickael
Egesipe, Anne-Laure
Tentillier, Noémie
Font, Laure
Ratnam, Monisha
Mottier, Lorene
Clavel, Mathieu
Le Roux-Bourdieu, Morgan
Fenyi, Alexis
Ollier, Romain
Chevalier, Elodie
Guilhot, Florence
Fuchs, Aline
Piorkowska, Kasia
Carlyle, Becky
Arnold, Steven E
Berry, James D
Luthi-Carter, Ruth
Adolfsson, Oskar
Pfeifer, Andrea
Kosco-Vilbois, Marie
Seredenina, Tamara
Afroz, Tariq
author_facet Audrain, Mickael
Egesipe, Anne-Laure
Tentillier, Noémie
Font, Laure
Ratnam, Monisha
Mottier, Lorene
Clavel, Mathieu
Le Roux-Bourdieu, Morgan
Fenyi, Alexis
Ollier, Romain
Chevalier, Elodie
Guilhot, Florence
Fuchs, Aline
Piorkowska, Kasia
Carlyle, Becky
Arnold, Steven E
Berry, James D
Luthi-Carter, Ruth
Adolfsson, Oskar
Pfeifer, Andrea
Kosco-Vilbois, Marie
Seredenina, Tamara
Afroz, Tariq
author_sort Audrain, Mickael
collection PubMed
description In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to the propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for the aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of the pharmacokinetic/pharmacodynamic effect for the monoclonal antibody, ACI-5891.9, in vivo and in vitro confirmed that a CSF concentration of ≍1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients.
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spelling pubmed-106449822023-11-03 Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF Audrain, Mickael Egesipe, Anne-Laure Tentillier, Noémie Font, Laure Ratnam, Monisha Mottier, Lorene Clavel, Mathieu Le Roux-Bourdieu, Morgan Fenyi, Alexis Ollier, Romain Chevalier, Elodie Guilhot, Florence Fuchs, Aline Piorkowska, Kasia Carlyle, Becky Arnold, Steven E Berry, James D Luthi-Carter, Ruth Adolfsson, Oskar Pfeifer, Andrea Kosco-Vilbois, Marie Seredenina, Tamara Afroz, Tariq Brain Commun Original Article In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to the propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for the aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of the pharmacokinetic/pharmacodynamic effect for the monoclonal antibody, ACI-5891.9, in vivo and in vitro confirmed that a CSF concentration of ≍1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients. Oxford University Press 2023-11-03 /pmc/articles/PMC10644982/ /pubmed/38025276 http://dx.doi.org/10.1093/braincomms/fcad306 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Audrain, Mickael
Egesipe, Anne-Laure
Tentillier, Noémie
Font, Laure
Ratnam, Monisha
Mottier, Lorene
Clavel, Mathieu
Le Roux-Bourdieu, Morgan
Fenyi, Alexis
Ollier, Romain
Chevalier, Elodie
Guilhot, Florence
Fuchs, Aline
Piorkowska, Kasia
Carlyle, Becky
Arnold, Steven E
Berry, James D
Luthi-Carter, Ruth
Adolfsson, Oskar
Pfeifer, Andrea
Kosco-Vilbois, Marie
Seredenina, Tamara
Afroz, Tariq
Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF
title Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF
title_full Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF
title_fullStr Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF
title_full_unstemmed Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF
title_short Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF
title_sort targeting amyotrophic lateral sclerosis by neutralizing seeding-competent tdp-43 in csf
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10644982/
https://www.ncbi.nlm.nih.gov/pubmed/38025276
http://dx.doi.org/10.1093/braincomms/fcad306
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