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）：本提案响应 NINDS 的 SBIR/STTR PHS 2006-2“为急性和慢性中枢神经系统损伤的有希望的疗法开发新的临床前测试”的征集。脊髓损伤 (SCI) 是一种毁灭性的创伤性中枢神经系统疾病，约 20 万美国人只能坐在轮椅上，其中三分之二的新受害者年龄在 30 岁以下。SCI 后的功能缺陷是由于轴突损伤或切断、神经元丧失造成的和神经胶质细胞，以及脱髓鞘。 SCI 病理学不仅取决于最初的机械损伤，还取决于继发过程，包括缺血、自由基形成、炎症和兴奋性毒性。目前，SCI尚无治愈方法，即使未经FDA批准，甲基强的松龙也是临床上唯一的选择。显然，迫切需要新的疗法来最大限度地减少灾难性后果并更有效地改善神经功能。我们开发了一种抗炎/神经保护肽 COG133，源自载脂蛋白 E (apoE) 的受体结合区域。我们的深入研究表明，小apoE模拟物通过以下可能的途径发挥重要的生物活性，消除继发性损伤并促进SCI的恢复：（1）抗炎； (2)减少过量的Ca2+内流，防止谷氨酸的兴奋性毒性； (3)减少自由基物种和一氧化氮的产生； (4) 促进髓磷脂碎片的清除，髓磷脂碎片可能抑制轴突再生； (5)通过输送胆固醇和保护少突胶质细胞促进髓鞘重建； (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 在已建立的多发性硬化症和创伤性颅脑损伤小鼠模型中具有神经保护作用，这些损伤性疾病与 SCI 有许多共同特征。我们假设 COG133 可能代表新一代 SCI 治疗药物，具有减少继发性损伤的神经退行性变和促进轴突再生和髓鞘再生的双重潜力。作为概念验证，在第一阶段提案中，我们将使用人类 SCI 的小鼠挫伤模型来测试 COG133 是否可以改善行为结果和病理读数。这项 I 期研究的完成将确定 COG133 是否是 SCI 的候选疗法。脊髓损伤 (SCI) 是一种严重的破坏性中枢神经系统创伤性疾病，约 20 万美国人只能坐在轮椅上，其中三分之二的新受害者年龄在 30 岁以下。令人遗憾的是，治疗 SCI 的需求严重未得到满足：甲泼尼龙是临床上唯一的选择，但效果可疑。现在，我们提出一种源自载脂蛋白 E (apoE) 的小合成肽，即 COG133，作为 SCI 的有前途的治疗候选药物。 COG133的设计和合成基于我们对apoE神经生物学作用的深入研究。我们的初步探索表明，COG133 可能通过多种机制对 SCI 后继发性损伤产生神经保护作用，也可能直接促进轴突再生，从而促进功能恢复。在这项 I 期研究中，我们将首先在 SCI 小鼠压迫模型中测试潜在的神经保护作用。该提案的完成可能会验证 COG133 是否是一种有前景的 SCI 治疗方法。

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