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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\u20101004\u20101239 is a potent, selective, insurmountable, and orally available first\u2010in\u2010class CXCR7 receptor antagonist. The effect of ACT\u20101004\u20101239 was evaluated in the myelin oligodendrocyte glycoprotein (MOG)\u2010induced experimental autoimmune encephalomyelitis (EAE) and the cuprizone\u2010induced demyelination mouse models. In addition, ACT\u20101004\u20101239 was assessed in a rat oligodendrocyte precursor cell (OPC) differentiation assay in vitro. In the MOG\u2010induced EAE model, ACT\u20101004\u20101239 treatment (10\u2010100\u00a0mg\/kg, twice daily, orally) showed a significant dose\u2010dependent reduction in disease clinical scores, resulting in increased survival. At the highest dose tested (100\u00a0mg\/kg, twice daily), ACT\u20101004\u20101239 delayed disease onset and significantly reduced immune cell infiltrates into the CNS and plasma neurofilament light chain concentration. Treatment with ACT\u20101004\u20101239 dose\u2010dependently increased plasma CXCL12 concentration, which correlated with a reduction of the cumulative disease score. Furthermore, in the cuprizone model, ACT\u20101004\u20101239 treatment significantly increased the number of mature myelinating oligodendrocytes and enhanced myelination in vivo. In vitro, ACT\u20101004\u20101239 promoted the maturation of OPCs into myelinating oligodendrocytes. These results provide evidence that ACT\u20101004\u20101239 both reduces neuroinflammation and enhances myelin repair substantiating the rationale to explore its therapeutic potential in a clinical setting.<\/jats:p>","DOI":"10.1096\/fj.202002465r","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T07:32:56Z","timestamp":1613806376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["ACT\u20101004\u20101239, a first\u2010in\u2010class CXCR7 antagonist with both immunomodulatory and promyelinating effects for the treatment of inflammatory demyelinating diseases"],"prefix":"10.1096","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8727-1142","authenticated-orcid":false,"given":"Laetitia","family":"Pouzol","sequence":"first","affiliation":[{"name":"Idorsia Pharmaceuticals Ltd. 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