ACT-1004-1239, a first-in-class CXCR7 antagonist with both immunomodulatory and promyelinating effects for the treatment of inflammatory demyelinating diseases.
Animals
Cell Differentiation
/ drug effects
Cuprizone
/ pharmacology
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental
/ immunology
Female
Immunomodulation
/ drug effects
Inflammation
/ drug therapy
Male
Mice, Inbred C57BL
Multiple Sclerosis
/ drug therapy
Myelin Sheath
/ drug effects
Myelin-Oligodendrocyte Glycoprotein
/ metabolism
Oligodendroglia
/ cytology
Receptors, CXCR
/ antagonists & inhibitors
Stem Cells
/ cytology
CXCR7
demyelinating diseases
experimental autoimmune encephalomyelitis
immunomodulation
myelin repair
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
07
11
2020
revised:
15
01
2021
accepted:
25
01
2021
entrez:
17
2
2021
pubmed:
18
2
2021
medline:
14
7
2021
Statut:
ppublish
Résumé
Current strategies for the treatment of demyelinating diseases such as multiple sclerosis (MS) are based on anti-inflammatory or immunomodulatory drugs. Those drugs have the potential to reduce the frequency of new lesions but do not directly promote remyelination in the damaged central nervous system (CNS). Targeting CXCR7 (ACKR3) has been postulated as a potential therapeutic approach in demyelinating diseases, leading to both immunomodulation by reducing leukocyte infiltrates and promyelination by enhancing myelin repair. ACT-1004-1239 is a potent, selective, insurmountable, and orally available first-in-class CXCR7 receptor antagonist. The effect of ACT-1004-1239 was evaluated in the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and the cuprizone-induced demyelination mouse models. In addition, ACT-1004-1239 was assessed in a rat oligodendrocyte precursor cell (OPC) differentiation assay in vitro. In the MOG-induced EAE model, ACT-1004-1239 treatment (10-100 mg/kg, twice daily, orally) showed a significant dose-dependent reduction in disease clinical scores, resulting in increased survival. At the highest dose tested (100 mg/kg, twice daily), ACT-1004-1239 delayed disease onset and significantly reduced immune cell infiltrates into the CNS and plasma neurofilament light chain concentration. Treatment with ACT-1004-1239 dose-dependently increased plasma CXCL12 concentration, which correlated with a reduction of the cumulative disease score. Furthermore, in the cuprizone model, ACT-1004-1239 treatment significantly increased the number of mature myelinating oligodendrocytes and enhanced myelination in vivo. In vitro, ACT-1004-1239 promoted the maturation of OPCs into myelinating oligodendrocytes. These results provide evidence that ACT-1004-1239 both reduces neuroinflammation and enhances myelin repair substantiating the rationale to explore its therapeutic potential in a clinical setting.
Identifiants
pubmed: 33595155
doi: 10.1096/fj.202002465R
doi:
Substances chimiques
Cmkor1 protein, mouse
0
Myelin-Oligodendrocyte Glycoprotein
0
Receptors, CXCR
0
Cuprizone
5N16U7E0AO
Banques de données
ClinicalTrials.gov
['NCT03869320', 'NCT04286750']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e21431Informations de copyright
© 2021 Idorsia Pharmaceuticals Ltd. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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