Novel Nontoxic Therapeutic Interventions for Autoimmune Inflammatory Disease

项目摘要/摘要 尽管自身免疫性疾病取得了进展和治疗方法，但对更安全的需求仍然没有得到满足。 以及针对个别患者量身定做的更有效的治疗方法。这些进步不可能 在我们的知识和对疾病机制的理解没有取得重大进展的情况下发生。 在自身免疫卓越中心的支持下，我们组建了一个 五年前的杰出合作地点成立了“范斯坦医学研究所” 自身免疫性疾病临床研究中心。我们中心的首要主题是 自身免疫性疾病中发生的组织损伤通常是多发性和多发性的 多余的炎症途径和介质(细胞因子)。我们仍然相信，一个 将与调节多种炎症介质的抗炎方法相关联 有更好的临床疗效，我们将寻找耐受性更好的药物 安全概况比目前可用的治疗方案更好。为此，我们现在 提出两项临床试验，一项针对系统性红斑狼疮的认知障碍，另一项针对青少年 类风湿关节炎。我们提议“改变”一种安全、广泛使用的血管紧张素的用途 一种跨越血脑屏障用于治疗认知障碍的抑制剂 影响了很多系统性红斑狼疮患者。在实验室里，这种药物已经被证明可以减少 小胶质细胞所致的神经元损伤。我们将使用先进的脑成像技术来评估 对SLE患者的影响。我们提出的第二项研究是使用“生物电子”医学 减少JIA(幼年特发性关节炎)儿童的关节炎。我们将激活 胆碱能抗炎途径通过刺激迷走神经的无创，非侵入性的 令人痛苦的温和电流。在实验室里，刺激迷走神经可以降低 产生炎性细胞因子。这两项研究都是为了评估疗效和安全性， 两者都伴随着综合的机制研究，以了解更多关于生物的 干预的效果。每一种都被设计用来识别潜在的反应生物标志物。 该中心将继续努力开展协作性创新临床试验，将1) 通过控制炎症性疾病和减少 器官损伤和功能障碍，2)有助于更好地了解 自身免疫性疾病和治疗反应的机制，3)导致个性化 治疗自身免疫性疾病的医学方法4)评估不会导致自身免疫性疾病的药物 临床上有意义的免疫抑制和5)进行协作创新临床试验 制药业不会追求这一点。

Project Summary/Abstract Despite advances and treatments in autoimmune disease, there remains an unmet need for safer and more effective therapies that are tailored to the individual patient. These advances cannot occur without significant advances in our knowledge and understanding of disease mechanisms. With support from the Autoimmunity Centers of Excellence, we assembled a consortium of outstanding collaborating sites 5 years ago to form “The Feinstein Institute for Medical Research Center for Clinical Research in Autoimmune Disease”. The overarching theme of our Center is that tissue injury occurring in autoimmune disease is often the end-result of multiple and often redundant inflammatory pathways and mediators (cytokines). We continue to believe that an anti-inflammatory approach that modulates multiple inflammatory mediators will be associated with greater clinical efficacy and we will seek agents with improved tolerability and a better safety profile than therapeutic options that are currently available. Towards this end, we now propose two clinical trials, one targeting cognitive impairment in SLE and the other in Juvenile Rheumatoid Arthritis. We are proposing to “repurpose” a safe, widely available angiotensin inhibitor that crosses the blood-brain-barrier for treatment of the cognitive impairment that affects so many patients with SLE. In the laboratory, this medication has been shown to reduce neuronal injury by microglia. We will use sophisticated brain imaging techniques to evaluate the effects in patients with SLE. The second study we propose is to use “bioelectronic" medicine to reduce arthritis in children with JIA (juvenile idiopathic arthritis). We will activate the cholinergic anti-inflammatory pathway by stimulating the vagus nerve with a non-invasive, non- painful mild electric current. In the laboratory, stimulating the vagus nerve reduces the production of inflammatory cytokines. Both studies are designed to evaluate efficacy and safety, and both are accompanied by integrated mechanistic studies to learn more about the biologic effects of the intervention. Each is also designed to identify potential biomarkers of response. This Center will continue to strive to conduct collaborative innovative clinical trials that will 1) promote improved patient outcomes through control of inflammatory disease and a reduction of organ damage and dysfunction, 2) result in a better understanding of the pathogenesis of autoimmune diseases and mechanisms for therapeutic responses, 3) lead to a personalized medicine approach to treatment of autoimmune disease 4) evaluate agents that do not cause clinically significant immunosuppresion and 5) conduct collaborative innovative clinical trials that would not be pursued by the pharmaceutical industry.