Development of Remyelinating Agents

描述(申请人提供)：多发性硬化症(MS)是年轻人的破坏性神经疾病之一，其病理特征是大脑和脊髓的炎症和脱髓鞘。超过一半的多发性硬化症患者对目前FDA批准的疾病修正治疗反应不佳。这种缺乏反应的部分原因可能是由于目前的治疗方法专门针对疾病的炎症阶段，但它们没有提供促进修复的活性。因此，髓鞘修复可能最大限度地促进神经和功能的恢复，并代表着一种最具吸引力的策略，为MS开发新的治疗方法，以满足这一严重未得到满足的医疗需求。我们之所以对开发基于载脂蛋白E的重髓磷脂药物感兴趣，是因为我们有以下独特的理解：1)载脂蛋白E是中枢神经系统中的主要载脂蛋白，调节与髓鞘形成相关的脂和胆固醇代谢；以及2)载脂蛋白E可能影响髓鞘形成细胞(少突胶质细胞及其前体细胞)的增殖、分化和在免疫攻击、炎症、兴奋毒性和氧化应激中的存活。Cognosci，Inc.创新设计了模拟apoE全蛋白生物活性的肽类化合物，在MS的EAE模型中也显示了治疗效果。在一项初步研究中，我们建议从以下几个方面考察我们的先导化合物COG112作为再髓鞘促进剂：1)特定目的：我们将在铜酮诱导的脱髓鞘模型中验证COG112潜在的促进再髓鞘形成的作用；2)特定目标2：我们将在铜环带模型中检测COG112治疗对膝状体内少突胶质细胞前体细胞(OPC)增殖和分化/成熟的影响；3)特殊目的3：我们将在OPC和小胶质细胞的混合培养中检测COG112是否可以防止炎症诱导的少突胶质前体细胞死亡。完成这一第一阶段的资助将产生临床前数据，以确定我们的COG化合物作为一种独特的脱髓鞘疾病MS的再髓鞘药物的效用，无论是作为当前免疫调节疗法的补充，还是作为抗炎本身，我们在这笔赠款中提出的COG化合物的再髓鞘特性可能会满足对MS恢复性治疗的巨大医疗需求。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is one of the devastating neurological diseases in young adults that is pathologically characterized by inflammation and demyelination in the brain and spinal cord. More than half of MS patients do not respond well to the current FDA-approved disease-modifying treatments. This lack of response may be due, in part, to the current therapeutics being specifically targeted to the inflammatory phase of the disease, but they do not deliver repair-promoting activity. Therefore, myelin repair may maximize both neurological and functional restoration, and represents a most attractive strategy for developing a new therapy for MS to address this critically unmet medical need. Our interest in developing apolipoprotein E-based remyelinating agents is derived from our unique understanding that 1) apoE is the principal apolipoprotein in the CNS modulating lipid and cholesterol metabolism relevant to myelination; and 2) apoE may affect myelin-forming cells (oligodendrocyte and its precursor cell) proliferation, differentiation and survival during immune attack, inflammation, excitotoxicity, and oxidative stress. Cognosci, Inc. has innovatively designed peptidochemicals to mimic the bioactivities of apoE holo-protein that also display therapeutic efficacy in EAE models of MS. With support of preliminary data in a pilot study, we propose to examine our lead compound COG112 as remyelination-promoting agent in the following aspects: 1) Specific Aim 1: We will verify the potential remyelination-promoting effect of COG112 in a cuprizone-induced demyelination model; 2) Specific Aim 2: We will examine the effect of COG112 treatment on OPC (Oligodendrocyte Precursor Cell) proliferation and differentiation/maturation within the corpus callosum in a cuprizone model; 3) Specific Aim 3: We will examine if COG112 can prevent inflammation-induced oligodendrocyte precursor cell death in a mixed culture of OPC and microglia. The completion of this Phase I grant will generate the preclinical data to establish the utility of our COG compound as a unique, remyelinating agent for the demyelinating disease, MS, either as a supplement to the current immune-modifying therapies, or as an anti-inflammatory itself, the remyelinating properties of COG compounds that we propose in this grant might fill the tremendous medical need for a restorative therapeutic for MS.