• In silico screening and precli...

Treffer: In silico screening and preclinical validation identify bavisant as a therapeutic candidate for multiple sclerosis.

Title:
In silico screening and preclinical validation identify bavisant as a therapeutic candidate for multiple sclerosis.
Authors:
Gacem N; Paris Brain Institute - Institut du Cerveau (ICM), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013 Paris, France., Bezukladova S; Division of Neuroscience, Vita-Salute San Raffaele University, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, 20129 Milan, Italy., Windener F; Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany., Karam T; Paris Brain Institute - Institut du Cerveau (ICM), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013 Paris, France., Ottoboni L; Division of Neuroscience, Vita-Salute San Raffaele University, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, 20129 Milan, Italy., Brambilla E; Division of Neuroscience, Vita-Salute San Raffaele University, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, 20129 Milan, Italy., Ruffini F; Division of Neuroscience, Vita-Salute San Raffaele University, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, 20129 Milan, Italy., Soman K; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA., Garcia-Diaz B; Paris Brain Institute - Institut du Cerveau (ICM), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013 Paris, France., Levy MJF; Paris Brain Institute - Institut du Cerveau (ICM), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013 Paris, France., Cui QL; Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada., Formato A; Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy., Deboux C; Paris Brain Institute - Institut du Cerveau (ICM), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013 Paris, France., Chazot J; Paris Brain Institute - Institut du Cerveau (ICM), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013 Paris, France., Panic R; Paris Brain Institute - Institut du Cerveau (ICM), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013 Paris, France., Albrecht S; Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany., Yilmaz EN; Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany., González RG; Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany., Eberini I; Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy., Olla S; Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042 Monserrato, Italy., Bresciani A; IRBM S.p.A., Pomezia, Rome 00071, Italy., Goebels N; Department of Neurology, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany., Zipp F; Department of Neurology, Focus Program Translational Neuroscience and Immunotherapy, Rhine-Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany., Agresti C; Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy., Antel J; Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada., Evercooren AB; Paris Brain Institute - Institut du Cerveau (ICM), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013 Paris, France., Kuhlmann T; Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany., Baranzini SE; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA., Panina-Bordignon P; Division of Neuroscience, Vita-Salute San Raffaele University, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, 20129 Milan, Italy., Nait-Oumesmar B; Paris Brain Institute - Institut du Cerveau (ICM), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013 Paris, France., Martino G; Division of Neuroscience, Vita-Salute San Raffaele University, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, 20129 Milan, Italy.
Source:
Science translational medicine [Sci Transl Med] 2026 Jan 21; Vol. 18 (833), pp. eads0633. Date of Electronic Publication: 2026 Jan 21.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
Imprint Name(s):
Original Publication: Washington, DC : American Association for the Advancement of Science
MeSH Terms:
Multiple Sclerosis*/drug therapy , Multiple Sclerosis*/pathology , Computer Simulation*, Animals ; Humans ; Drug Evaluation, Preclinical ; Oligodendroglia/drug effects ; Oligodendroglia/pathology ; Oligodendroglia/metabolism ; Encephalomyelitis, Autoimmune, Experimental/drug therapy ; Encephalomyelitis, Autoimmune, Experimental/pathology ; Mice ; Neuroprotective Agents/therapeutic use ; Neuroprotective Agents/pharmacology ; Disease Models, Animal ; Myelin Sheath/drug effects ; Myelin Sheath/metabolism ; Mice, Inbred C57BL ; Reproducibility of Results ; Female ; Remyelination/drug effects ; Neurons/drug effects ; Neurons/pathology ; Axons/drug effects ; Axons/pathology
Substance Nomenclature:
0 (Neuroprotective Agents)
Entry Date(s):
Date Created: 20260121 Date Completed: 20260121 Latest Revision: 20260121
Update Code:
20260122
DOI:
10.1126/scitranslmed.ads0633
PMID:
41564155
Database:
MEDLINE

Weitere Informationen

Current treatments for multiple sclerosis (MS) are insufficient to delay the neurodegenerative process that is the main cause of disability progression in patients with MS. Therapeutics aimed at supporting myelin regeneration and neuroprotection are thus a major unmet medical need for the progressive forms of MS. To address this, we developed a strategy combining in silico screening of more than 1500 repurposed compounds with a validation pipeline of models, encompassing rodent and human in vitro assays as well as mouse models of demyelination/remyelination. From the initial library, 273 drugs were prioritized in silico on the basis of the predicted effects on myelination and neuroprotection, and among them, 160 were potentially nontoxic. We identified 32 molecules that exerted a promyelinating and a neuroprotective action on rodent and human oligodendroglia and neurons. Our data identified classes of compounds with potentially distinct mechanisms of action that may foster remyelination and neuroprotection. The therapeutic activity of one selected drug, the histamine receptor H3 antagonist bavisant, was further validated in mouse models of demyelination and axonal injury reproducing some key pathological features occurring in MS. Our in vivo studies demonstrated that bavisant promoted remyelination and neuroprotection when administered to LPC-treated, cuprizone-fed, or MOG-induced EAE mice, as well as in a human oligodendroglia chimeric mouse model of demyelination/remyelination. These findings provide proof-of-concept validation for bavisant as a candidate for neuroprotective clinical trials in MS.