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

Autor:	Audrain M; Research, AC Immune SA, 1015 Lausanne, Switzerland., Egesipe AL; Research, AC Immune SA, 1015 Lausanne, Switzerland., Tentillier N; Research, AC Immune SA, 1015 Lausanne, Switzerland., Font L; Research, AC Immune SA, 1015 Lausanne, Switzerland., Ratnam M; Research, AC Immune SA, 1015 Lausanne, Switzerland., Mottier L; Research, AC Immune SA, 1015 Lausanne, Switzerland., Clavel M; Research, AC Immune SA, 1015 Lausanne, Switzerland., Le Roux-Bourdieu M; Research, AC Immune SA, 1015 Lausanne, Switzerland., Fenyi A; Research, AC Immune SA, 1015 Lausanne, Switzerland., Ollier R; Research, AC Immune SA, 1015 Lausanne, Switzerland., Chevalier E; Research, AC Immune SA, 1015 Lausanne, Switzerland., Guilhot F; Research, AC Immune SA, 1015 Lausanne, Switzerland., Fuchs A; Research, AC Immune SA, 1015 Lausanne, Switzerland., Piorkowska K; Research, AC Immune SA, 1015 Lausanne, Switzerland., Carlyle B; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK., Arnold SE; Department of Neurology and the Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA., Berry JD; Sean M. Healey & AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Luthi-Carter R; Research, AC Immune SA, 1015 Lausanne, Switzerland., Adolfsson O; Research, AC Immune SA, 1015 Lausanne, Switzerland., Pfeifer A; Research, AC Immune SA, 1015 Lausanne, Switzerland., Kosco-Vilbois M; Research, AC Immune SA, 1015 Lausanne, Switzerland., Seredenina T; Research, AC Immune SA, 1015 Lausanne, Switzerland., Afroz T; Research, AC Immune SA, 1015 Lausanne, Switzerland.
Jazyk:	angličtina
Zdroj:	Brain communications [Brain Commun] 2023 Nov 03; Vol. 5 (6), pp. fcad306. Date of Electronic Publication: 2023 Nov 03 (Print Publication: 2023).
DOI:	10.1093/braincomms/fcad306
Abstrakt:	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. Competing Interests: T.A. and T.S. are co-inventors on a patent application, publication number WO2020/234473. R.O., T.A. and T.S. are co-inventors on a patent application, publication number WO2022/034228. M.A., L.F., R.O., M.R., M.L.R.-B., E.C., A.F. , A.F.U, K.P., R.L.-C., O.A., A.P., M.K.-V., T.S. and T.A. are employees of AC Immune and entitled to options and/or shares. N.T., A.-L.E., M.C. and L.M. were employees of AC Immune at the time of this study. The other authors declare no competing interests. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu