Novel therapy for multiple sclerosis

描述(由申请人提供)：本提案回应了NINDS关于“开发预防、阻止或逆转自身免疫性神经疾病(如多发性硬化症)的疗法”的SBIR/STTRPHS 2005-2的征集。多发性硬化症(MS)是一种慢性炎症性中枢神经系统自身免疫性疾病(CNS)，以大脑和脊髓白质区域脱髓鞘为特征，影响美国超过35万人和全球250万人。目前，多发性硬化症还没有治愈方法，FDA批准的治疗方法专注于改善疾病的炎性成分，而不是预防不可逆转的组织损伤，这是多发性硬化症的标志和慢性残疾的原因。因此，对多发性硬化症的治疗需求尚未得到满足，这种疗法不仅能发挥抗炎作用，而且还能预防/改善导致多发性硬化症患者终身残疾的不可逆转的神经损伤。我们开发了一种来源于载脂蛋白E(ApoE)受体结合区的抗炎/神经保护多肽COG133，它1)抑制小胶质细胞的激活和炎症介质(如TNFa、IL-6、NO)的分泌；2)保护原代培养的神经元免受谷氨酸兴奋毒性和氧化应激的影响；3)启动巨噬细胞信号级联反应，抑制巨噬细胞的激活；4)抑制小鼠静脉注射内毒素后全身和CMS炎症细胞因子的释放；5)内毒素激活抑制人全血中肿瘤坏死因子-α和IL-6的分泌；6)在闭合性脑损伤小鼠模型中表现出神经保护作用。这些数据表明，COG133同时具有抗炎和神经保护作用，因此可能代表着治疗这种疾病的炎症和神经退行性变方面所需的新一代MS治疗药物。作为概念的证明，在这个第一阶段的提案中，我们将使用人类MS的小鼠EAE模型来测试COG133是否可以(1)改善MOG诱导的C57BL/6小鼠EAE的神经损害；以及(2)降低PLP诱导的SJL小鼠EAE复发缓解模型的复发率。COG133治疗对中枢神经系统外周血白细胞浸润的影响也将被研究，这是EAE和MS发病的关键步骤。总之，我们的总体目标是开发一种治疗多发性硬化症的新疗法。与目前具有简单抗炎作用的单一疗法相比，COG133的抗炎和神经保护作用可能是治疗多发性硬化症更强大的双重治疗潜力的基础。

DESCRIPTION (provided by applicant): This proposal responds to the solicitation of SBIR/STTR PHS 2005-2 for "development of therapies to prevent, arrest or reverse autoimmune neurological disorder such as multiple sclerosis" by NINDS. Multiple sclerosis (MS) is a chronic inflammatory autoimmune disorder of the central nervous system; CNS) characterized by demyelination in areas of white matter of the brain and spinal cord that affects more than 350,000 people in the United States (US) and 2.5 million worldwide. Currently, there is no cure for MS, and FDA-approved therapies are focused on ameliorating the inflammatory component of the disease, and not Prevention of the irreversible tissue damage that is the hallmark of MS and the cause of chronic disability. Thus, there is an unmet need for a therapy for MS that not only exerts anti-inflammatory effects, but that also prevents/ameliorates the irreversible neurological damage responsible for the lifelong disability faced by the MS patient. We have developed an anti-inflammatory/neuroprotective peptide, COG133 derived from the receptor binding region of apolipoprotein E (apoE), which 1) suppressed microglial activation and secretion of inflammatory mediators (e.g., TNFa, IL-6, nitric oxide); 2) protected primary culture neurons from glutamate excitotoxicity and oxidative stress; 3) initiated a macrophage signaling cascade and suppressed macrophage activation 4) suppressed the release of systemic, as well as CMS inflammatory cytokines elicited following IV administration of LPS in mice; 5) suppressed secretion of TNF-a and IL-6 in whole human blood is activated with LPS; and 6) exhibited neuroprotective activity in a mouse model of closed head injury. These data indicate that COG133 possesses both anti-inflammatory and neuroprotective effects, and as such may represent the new generation MS therapeutic needed to treat both the inflammatory and neurodegenerative aspects of this disease. As a proof of concept, in this phase I proposal, we will use the murine EAE model of human MS to test whether COG133, given after onset of diseases, can (1) ameliorate neurological impairment in MOG-induced EAE in C57BL/6 mice; and (2) reduce the rate of relapses in PLP-elicited relapsing-remitting model of EAE in SJL mice. The influence of COG133 treatment on peripheral leukocytes infiltration into the CNS, which is the critical step for the pathogenesis of EAE and MS, will also be investigated. In summary, our overall goal is to develop a novel therapy for MS. The anti-inflammatory and neuroprotective effects of COG133 may underlie more powerful, dual therapeutic potential for treatment of MS than current monotherapies with simple anti-inflammatory action.