多发性硬化症 (MS) 是一种影响中枢神经系统 (CNS) 的自身免疫性疾病，免疫系统攻击髓鞘，导致神经元死亡。虽然有几种疾病缓解疗法可用于治疗多发性硬化症，但这些疗法并非普遍有效，也不能阻止疾病进展。需要针对疾病特定方面的更个性化的长期治疗方案，例如减少复发频率、延缓残疾积累、解决影响日常功能的症状，以及可以促进神经保护和修复的疗法。嵌合抗原受体 (CAR) T 细胞疗法通过静脉 (IV) 注射由 CAR 提供的具有高特异性的确定剂量的 T 细胞，彻底改变了癌症治疗。使用抑制性调节性 T 细胞 (Treg) 诱导持久耐受的自体 CAR T 细胞疗法将是患者的理想治疗方法。因此，我们通过将CAR引入Treg细胞来治疗多发性硬化症患者，从而扩大了CAR-T细胞的应用。我们为 MS 患者开发了一种髓磷脂少突胶质细胞糖蛋白 (MOG) 特异性 CAR Treg 细胞疗法。 MOG 在髓鞘的外膜上表达，髓鞘是神经周围形成的绝缘层，使其成为 CAR Treg 治疗的理想靶点。我们的主要候选药物是第二代 CAR，由从大型人类文库筛选的抗 MOG scFv 组成。在体外，我们展示了 CAR 依赖性功能，并使用被动 EAE 小鼠模型显示了体内功效。此外，MOG-CAR Tregs 具有非常低的强直信号传导和理想的信噪比，从而产生高效的 CAR。总之，我们的数据表明 MOG-CAR Tregs 是一种有前途的 MS 治疗选择，有可能诱导患者持久耐受。© 2024。作者。

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.© 2024. The Author(s).