Novel Restorative Therapy For Spinal Cord Injury

脊髓损伤的新型恢复疗法

• 批准号: 7225714
• 负责人: FENG-QIAO LI
• 金额: $ 30.5万
• 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: 2006-09-25 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225714
• 关键词: aging; apolipoprotein E; assistive device /technology; brain injury; cholesterol; genes; glutamates; human; inflammation; injury; model; multiple sclerosis; myelin; peptides; regeneration; role; spinal cord injury

DESCRIPTION (provided by applicant): This proposal responds to the solicitation of SBIR/STTR PHS 2006-2 for "Develop new preclinical testing for promising therapies for acute and chronic central nervous system injury" by NINDS. Spinal cord injury (SCI) is a devastating traumatic CNS disorder confined about 200,000 Americans on wheelchairs, which two-thirds of the new victims are under the age of 30. Functional deficits following SCI result from damage to or severance of axons, loss of neurons and glia, and demyelination. SCI pathology is determined not only by the initial mechanical insult, but also by secondary processes including ischemia, free-radical formation, inflammation, and excitotoxicity. Currently, there is no cure for SCI, and methylprednisolone is the only choice on clinic, even without FDA approval. Clearly, novel therapies are urgently needed to maximally reduce the disastrous outcome and more effectively improve neurological functions. We have developed an anti-inflammatory/neuroprotective peptide, COG133 derived from the receptor-binding region of apolipoprotein E (apoE). Our intensive studies revealed that the small apoE-mimetic exerts significant bioactivities relevant to eliminate the secondary damage and foster the recovery of SCI in the following possible pathways: (1) anti-inflammation; (2) reducing excessive Ca2+ influx and protecting against excitotoxicity of glutamate; (3) reducing the production of free radical species and nitric oxide; (4) facilitate the removal of myelin debris, which may inhibit axonal regeneration; (5) promote the reconstruction of myelin sheath by delivering cholesterol and protecting oligodendrocytes; (6) promote axonal regeneration via neurotrophic effect. Our preliminary data showed that COG133 is neuroprotective in established murine models of multiple sclerosis and traumatic head injury, injurious conditions which share many common features with SCI. We hypothesize that COG133 may represent a new generation SCI therapeutic with the dual potentials of diminishing neurodegeneration of secondary damage and promoting axonal regeneration and remyelination. As a proof of concept, in this phase I proposal, we will use the murine contusion model of human SCI to test whether COG133 can improve behavioral outcome and pathological readout. The complete of this Phase I study will determine whether COG133 is a candidate therapy for SCI. Spinal cord injury (SCI) is a major devastating traumatic CNS disorder confined about 200,000 Americans on wheelchairs, which two-thirds of the new victims are under the age of 30. There is a critically unmet need for cure of SCI with the woeful fact that methylprednisolone is the only choice on clinic with suspicious effects. Now, we propose a small synthetic peptide derived from apolipoprotein E (apoE), namely COG133, as a promising therapeutic candidate for SCI. The design and synthesis of COG133 is based on our intensive studies on the neurobiological roles of apoE. Our pilot exploration indicates that COG133 may represent a neuroprotective effect through multiple mechanisms underlying the secondary damage after SCI and may also directly promote axonal regeneration and thus foster the functional recovery. We will test the potential neuroprotective effect in a mouse compression model of SCI first in this Phase I study. The complete of this proposal may validate whether COG133 is a promising therapy for SCI.

描述（由申请人提供）：该提案对SBIR/STTR PHS 2006-2的征集作出响应，以“开发新的临床前测试，以实现NINDS的急性和慢性中枢神经系统损伤的有前途的疗法”。脊髓损伤（SCI）是一种毁灭性的创伤性中枢神经系统疾病，限制在轮椅上约20万美国人，三分之二的新受害者年龄在30岁以下。SCI后SCI的功能缺陷是由于轴突损坏或脱离神经元的损坏，神经元和GLIA的丧失和脱氧而导致的。 SCI病理不仅取决于初始的机械侮辱，还取决于包括缺血，自由基形成，炎症和兴奋性毒性在内的次要过程。当前，尚无SCI治疗，即使未经FDA批准，甲基丙糖酮也是诊所的唯一选择。显然，迫切需要新的疗法来最大程度地减少灾难性结果并更有效地改善神经功能。我们已经开发了一种抗炎/神经保护肽，该肽是源自载脂蛋白E（APOE）的受体结合区域的COG133。我们的密集研究表明，小型APOE模仿具有与消除继发损伤相关的重要生物活性，并在以下可能的途径中促进了SCI的恢复：（1）抗炎； （2）减少过量的Ca2+流入并预防谷氨酸兴奋性毒性； （3）减少自由基物种和一氧化氮的产生； （4）促进去除髓磷脂碎屑，这可能会抑制轴突再生； （5）通过递送胆固醇并保护少突胶质细胞来促进髓鞘的重建； （6）通过神经营养作用促进轴突再生。我们的初步数据表明，COG133在多发性硬化症和创伤性头部损伤的已建立的鼠模型中具有神经保护作用，有害状况与SCI具有许多常见特征。我们假设COG133可能代表新一代的SCI治疗性，其双重潜力减少了二次损伤并促进轴突再生和再髓系。作为概念证明，在这一阶段的提案中，我们将使用人类SCI的鼠挫伤模型来测试COG133是否可以改善行为结果和病理读数。本阶段I研究的完整将确定COG133是否是SCI的候选疗法。脊髓损伤（SCI）是限制在轮椅上约20万美国人的主要毁灭性创伤中枢神经系统疾病，其中三分之二的新受害者年龄在30岁以下。对于甲基证明是甲基苯甲酸盐是具有怀疑作用的临床唯一的选择，因此对SCI的治愈方法毫无满意。现在，我们提出了一种源自载脂蛋白E（APOE）的小合成肽，即COG133，作为SCI的有前途的治疗候选者。 COG133的设计和合成是基于我们对APOE神经生物学作用的深入研究。我们的飞行员探索表明，COG133可以通过SCI后二次损伤的多种机制代表神经保护作用，并且也可以直接促进轴突再生，从而促进功能恢复。我们将在本I阶段研究中首先在SCI小鼠压缩模型中测试潜在的神经保护作用。该提案的完整可能验证COG133是否是SCI的有前途的疗法。

项目成果

Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice.

• DOI: 10.4172/2155-9562.s12-010
• 发表时间: 2013-04
• 期刊: Journal of neurology & neurophysiology
• 作者: Gu Z;Li F;Zhang YP;Shields LB;Hu X;Zheng Y;Yu P;Zhang Y;Cai J;Vitek MP;Shields CB
• 通讯作者: Shields CB