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）慢性炎症性疾病，其特征为髓鞘丢失、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，在美国影响约35万人，在全球影响超过100万人。目前的MS疾病修饰疗法（DMT）具有有限的疗效和不良毒性，强调需要基于靶向潜在疾病机制的新方法。 p38丝裂原活化激酶（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，目前正在临床上探索抑制p38 MAPK作为这些疾病的DMT。然而，p38 MAPK在MS（或MS模型）的病理生理学中的作用及其作为治疗靶点的潜力尚未研究。 使用实验性变态反应性脑脊髓炎（EAE），MS的主要自身免疫模型，我们测试了抑制p38 MAPK是否可以影响EAE易感性和疾病进展。用药理学p38 MAPK抑制剂SB 203580治疗雌性小鼠，如果在临床体征发作时给药，则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。这些结果表明，性别特异性因素有助于SB 203580介导的p38 MAPK活性抑制和EAE易感性。 在本申请中，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治疗反应中性别二型性的基础。了解药物作用机制可能为MS治疗提供新的，更具体的药物靶点。关于SB 203580的功效的性别二分法是特别重要的，因为许多自身免疫性疾病，包括MS，在疾病易感性方面表现出女性特异性的两性异形。SB 203580完全能够选择性抑制女性疾病的发现提供了选择性靶向增加的女性MS患者群体的独特DMT的可能性。 据我们所知，没有研究评估DMT抑制MS中p38 MAPK的潜力，尽管事实上许多靶向该途径的化合物已经被批准用于其他自身免疫性疾病的2期临床试验。此外，相对较少的研究集中在MS或其模型的治疗反应的性别差异的基础上。抑制p38 MAPK通路不仅可以提供一种新的DMT，其选择性地靶向增加的女性MS患者群体，而且还可能通过揭示治疗干预的新靶点，提供与MS的其他DMT开发相关的机制见解。

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.