Novel therapy for multiple sclerosis

多发性硬化症的新疗法

• 批准号: 7108087
• 负责人: FENG-QIAO LI
• 金额: $ 24.89万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-10 至 2007-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108087
• 关键词: blood; cytokine; emotions; glutamates; human; interferon beta; lead; macrophage; model; multiple sclerosis; myelin; neurons; oligodendroglia; peptides; secretion

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.

描述（由申请人提供）：该提案对SBIR/STTR PHS 2005-2的征集作出反应，以“开发用于预防，阻止或逆转自身免疫性神经系统疾病，例如多发性硬化症，例如多发性硬化症”。多发性硬化症（MS）是中枢神经系统的慢性炎症自身免疫性疾病。 CNS）以脱髓鞘形式在大脑和脊髓的脊髓区域脱髓鞘，在全球影响35万人（美国）和250万人。当前，尚无MS的治愈方法，FDA批准的疗法的重点是改善该疾病的炎症成分，而不是预防MS的标志和慢性残疾的原因。因此，对MS的治疗不仅需要施加抗炎作用，而且还可以防止/改善导致MS患者终身残疾的不可逆神经系统损害。我们已经开发了一种源自载脂蛋白E（APOE）的受体结合区（APOE）的抗炎/神经保护肽，COG133（APOE）抑制了炎症介质的小胶质细胞激活和分泌（例如TNFA，TNFA，IL-6，IL-6，一氧化物）； 2）保护原发性培养神经元免受谷氨酸兴奋性和氧化应激； 3）启动巨噬细胞信号级联并抑制巨噬细胞激活4）抑制了全身性的释放，以及在小鼠IV施用LPS后引起的CMS炎性细胞因子； 5）在整个人类血液中抑制TNF-A和IL-6的分泌被LP激活； 6）在闭合头部损伤的小鼠模型中表现出神经保护活性。这些数据表明COG133具有抗炎和神经保护作用，因此可能代表治疗该疾病的炎症性和神经退行性方面所需的新一代MS治疗性。作为概念证明，在这一阶段的提案中，我们将使用人类MS的鼠EAE模型来测试COG133在疾病发作后是否可以（1）在C57BL/6小鼠中减轻MOG诱导的EAE的神经功能障碍； （2）降低了SJL小鼠中EAE的PLP引起的复发模型中的复发率。 COG133处理对CNS外周血细胞浸润的影响，这是EAE和MS发病机理的关键步骤。总而言之，我们的总体目标是为MS开发新的疗法。 COG133的抗炎和神经保护作用可能比具有简单的抗炎作用的当前单层比目前的单层更强大，双重治疗潜力。