p38 MAPK as a female-specific druggable target in CNS autoimmune disease

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性炎症性疾病，其特征是髓磷脂缺失、不同程度的轴突损伤和进行性神经功能障碍。 MS 是年轻人和青少年最常见的致残性神经系统疾病，影响美国约 350,000 人，全球超过 100 万人。目前的多发性硬化症疾病缓解疗法 (DMT) 疗效有限且具有不良毒性，这凸显了需要基于针对潜在疾病机制的新方法。 p38 丝裂原激活激酶 (MAPK) 是类风湿性关节炎 (RA) 和克罗恩病等疾病中自身免疫/炎症反应的中心分子，目前临床上正在探索抑制 p38 MAPK 作为这些疾病的 DMT。然而，p38 MAPK 在 MS（或 MS 模型）病理生理学中的作用及其作为治疗靶点的潜力尚未得到研究。 使用实验性过敏性脑脊髓炎 (EAE)（MS 的主要自身免疫模型），我们测试了 p38 MAPK 的抑制是否会影响 EAE 易感性和疾病进展。用药理学 p38 MAPK 抑制剂 SB203580 治疗雌性小鼠，如果在临床症状出现时给药，可以完全预防疾病或停止疾病。引人注目的是，雄性小鼠对治疗完全没有反应。这些发现表明，性别特异性因素有助于 SB203580 介导的 p38 MAPK 活性抑制和 EAE 易感性。 在此应用中，我们建议：1) 确定 EAE 中 p38 MAPK 抑制的分子和细胞机制；2) 确定 SB 治疗反应中性别二态性的基础。了解药物作用机制可能为多发性硬化症治疗提供新的、更具体的药物靶点。 SB203580 功效的性别二分法尤其重要，因为包括 MS 在内的许多自身免疫性疾病在疾病易感性方面表现出女性特有的性别二态性。 SB203580 完全能够选择性抑制女性疾病的发现为选择性针对不断增加的女性多发性硬化症患者群体的独特 DMT 提供了可能性。 据我们所知，尚无研究评估 DMT 在 MS 中抑制 p38 MAPK 的潜力，尽管许多针对该途径的化合物已被批准用于其他自身免疫性疾病的 2 期临床试验。此外，相对较少的研究关注多发性硬化症或其模型治疗反应中性别差异的基础。 p38 MAPK 通路的抑制不仅可以提供一种新型 DMT，选择性地针对不断增加的女性 MS 患者群体，而且还可能通过发现治疗干预的新靶标，为开发 MS 的其他 DMT 提供相关的机制见解。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by myelin loss, varying degrees of axonal damage, and progressive neurological dysfunction. MS is the most common disabling neurologic disease of young adults and adolescents affecting ~350,000 individuals in the United States and more than 1 million individuals worldwide. Current MS disease-modifying therapies (DMTs) have limited efficacy and untoward toxicities, underscoring the need for new approaches based on targeting underlying disease mechanisms. The p38 mitogen-activated kinase (MAPK) is a central molecule in autoimmune/inflammatory responses in diseases such as rheumatoid arthritis (RA) and Crohn's disease, and inhibition of p38 MAPK is currently being explored clinically as a DMT for these diseases. However, the role of p38 MAPK in the pathophysiology of MS (or MS models) and its potential as a therapeutic target has not been investigated. Using experimental allergic encephalomyelitis (EAE), the principal autoimmune model of MS, we tested whether inhibition of p38 MAPK can influence EAE susceptibility and disease progression. Treatment of female mice with the pharmacological p38 MAPK inhibitor, SB203580, either completely prevented disease or halted disease if administered at the onset of clinical signs. Strikingly, male mice were completely unresponsive to treatment. These findings suggest that sex-specific factors contribute to SB203580 mediated inhibition of p38 MAPK activity and EAE susceptibility. In this application, we propose to: 1) determine the molecular and cellular mechanisms targeted by p38 MAPK inhibition in EAE and 2) determine the basis of the sexual dimorphism in the therapeutic response to SB. Understanding the mechanisms of drug action is likely to provide novel, more specific drug targets for MS therapy. The gender dichotomy with regard to efficacy of SB203580 is particularly important, since many autoimmune diseases, including MS, exhibit a female-specific sexual dimorphism in disease susceptibility. The finding that SB203580 is fully capable of selectively inhibiting disease in females provides for the possibility of a unique DMT that selectively targets the increasing female MS patient population. No study to our knowledge has evaluated the DMT potential of inhibiting p38 MAPK in MS, despite the fact that many compounds targeting this pathway are already approved for phase 2 clinical trials in other autoimmune diseases. Further, relatively few studies focus on the basis of sex differences in therapeutic responses in MS or its models. Inhibition of the p38 MAPK pathway may not only provide a novel DMT which selectively targets the increasing female MS patient population, but also will likely provide mechanistic insight relevant to development of additional DMTs for MS, by uncovering new targets for therapeutic intervention.