Current treatments in multiple sclerosis (MS) are modulating the inflammatory component of the disease, but no drugs are currently available to repair lesions. Our study identifies in MS patients the overexpression of Plexin-A1, the signalling receptor of the oligodendrocyte inhibitor Semaphorin 3A. Using a novel type of peptidic antagonist, we showed the possibility to counteract the Sema3A inhibitory effect on oligodendrocyte migration and differentiation in vitro when antagonizing Plexin-A1. The use of this compound in vivo demonstrated a myelin protective effect as shown with DTI-MRI and confirmed at the histological level in the mouse cuprizone model of induced demyelination/remyelination. This effect correlated with locomotor performances fully preserved in chronically treated animals. The administration of the peptide also showed protective effects, leading to a reduced severity of demyelination in the context of experimental autoimmune encephalitis (EAE). Hence, the disruption of the inhibitory microenvironmental molecular barriers allows normal myelinating cells to exert their spontaneous remyelinating capacity. This opens unprecedented therapeutic opportunity for patients suffering a disease for which no curative options are yet available.

中文翻译：

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少突胶质细胞中Sema3A / Plexin-A1抑制信号的破坏是促进髓鞘再生的一种治疗策略。

多发性硬化症（MS）的当前治疗方法正在调节疾病的炎症成分，但目前尚无可用于修复病变的药物。我们的研究确定了MS患者中Plexin-A1的过表达，Plexin-A1是少突胶质细胞抑制剂Semaphorin 3A的信号传导受体。使用一种新型的肽类拮抗剂，我们显示了在对抗Plexin-A1时抵消Sema3A对体外少突胶质细胞迁移和分化的抑制作用的可能性。如DTI-MRI所示，该化合物在体内的使用显示出髓磷脂保护作用，并且在诱导的脱髓鞘/髓鞘再生的小鼠铜酮模型中在组织学水平上得到证实。这种作用与在长期治疗的动物中完全保留的运动能力有关。肽的给药还显示出保护作用，导致在实验性自身免疫性脑炎（EAE）的情况下脱髓鞘的严重程度降低。因此，抑制性微环境分子屏障的破坏使正常的髓鞘细胞发挥其自发的髓鞘再生能力。这为患有尚无治疗选择的疾病的患者提供了前所未有的治疗机会。