Multiple sclerosis (MS) is a debilitating autoimmune disease that impacts millions of patients worldwide, disproportionately impacting women (4:1), and often presenting at highly productive stages of life. This disease affects the spinal cord and brain and is characterized by severe neuroinflammation, demyelination, and subsequent neuronal damage, resulting in symptoms like loss of mobility. While untargeted and pan-immunosuppressive therapies have proven to be disease-modifying and manage (or prolong the time between) symptoms in many patients, a significant fraction are unable to achieve remission. Recent work has suggested that targeted neuroinflammation mitigation through selective inflammasome inhibition can offer relief to patients while preserving key components of immune function. Here, we show a screening of potential therapeutic targets using inflammasome-inhibiting Nanoligomers (NF-κB1, TNFR1, TNF-α, IL-6) that meet or far-exceed commercially available small-molecule counterparts like ruxolitinib, MCC950, and deucravacitinib. Using the human brain organoid model, top Nanoligomer combinations (NF-κB1 + TNFR1: NI111, and NF-κB1 + NLRP3: NI112) were shown to significantly reduce neuroinflammation without any observable negative impact on organoid function. Further testing of these top Nanoligomer combinations in an aggressive experimental autoimmune encephalomyelitis (EAE) mouse model for MS using intraperitoneal (IP) injections showed that NF-κB1 and NLRP3 targeting Nanoligomer combination NI112 rescues mice without observable loss of mobility or disability, minimal inflammation in brain and spinal cord histology, and minimal to no immune cell infiltration of the spinal cord and no demyelination, similar to or at par with mice that received no EAE injections (negative control). Mice receiving NI111 (NF-κB1 + TNFR1) also showed reduced neuroinflammation compared to saline (sham)-treated EAE mice and at par/similar to other inflammasome-inhibiting small molecule treatments, although it was significantly higher than NI112 leading to subsequent worsening clinical outcomes. Furthermore, treatment with an oral formulation of NI112 at lower doses showed a significant reduction in EAE severity, albeit with higher variance owing to administration and formulation/fill-and-finish variability. Overall, these results point to the potential of further development and testing of these inflammasome-targeting Nanoliogmers as an effective neuroinflammation treatment for multiple neurodegenerative diseases and potentially benefit several patients suffering from such debilitating autoimmune diseases like MS.

中文翻译：

---

使用炎症小体抑制纳米寡聚物缓解靶向神经炎症在实验性自身免疫性脑脊髓炎小鼠模型中具有治疗作用

多发性硬化症 (MS) 是一种使人衰弱的自身免疫性疾病，影响着全世界数以百万计的患者，其中对女性的影响尤为严重 (4:1)，并且通常出现在生命的高产阶段。这种疾病影响脊髓和大脑，其特点是严重的神经炎症、脱髓鞘和随后的神经元损伤，导致活动能力丧失等症状。虽然非靶向疗法和泛免疫抑制疗法已被证明可以缓解疾病并控制（或延长）许多患者的症状（或延长症状之间的时间），但很大一部分患者无法实现缓解。最近的研究表明，通过选择性炎症体抑制来缓解有针对性的神经炎症可以缓解患者的症状，同时保留免疫功能的关键组成部分。在这里，我们展示了使用炎症小体抑制纳米寡聚物（NF-κB1、TNFR1、TNF-α、IL-6）对潜在治疗靶点的筛选，这些纳米寡聚物达到或远远超过了市售小分子对应物，如鲁索替尼、MCC950 和 deucravacitinib。使用人脑类器官模型，顶级纳米低聚物组合（NF-κB1 + TNFR1：NI111 和 NF-κB1 + NLRP3：NI112）可显着减少神经炎症，且对类器官功能没有任何可观察到的负面影响。使用腹膜内 (IP) 注射在侵袭性实验性自身免疫性脑脊髓炎 (EAE) 小鼠模型中对这些顶级纳米寡聚体组合进行进一步测试表明，靶向纳米寡聚体组合 NI112 的 NF-κB1 和 NLRP3 可以拯救小鼠，而没有明显丧失活动能力或残疾，炎症最小化。大脑和脊髓组织学，脊髓的免疫细胞浸润极少甚至没有，并且没有脱髓鞘，与未接受 EAE 注射的小鼠相似或相当（阴性对照）。与生理盐水（假手术）治疗的 EAE 小鼠相比，接受 NI111（NF-κB1 + TNFR1）的小鼠也表现出神经炎症减少，并且与其他炎症小体抑制小分子治疗相当/相似，尽管它显着高于 NI112，导致随后的临床恶化结果。此外，较低剂量的 NI112 口服制剂治疗显示 EAE 严重程度显着降低，尽管由于给药和制剂/填充和完成的差异而导致差异较大。总体而言，这些结果表明，进一步开发和测试这些靶向炎症体的纳米寡聚体作为多种​​神经退行性疾病的有效神经炎症治疗方法的潜力，并可能使数名患有多发性硬化症等使人衰弱的自身免疫性疾病的患者受益。