Novel Restorative Therapy For Spinal Cord Injury

描述（由申请人提供）：本提案响应了SBIR/STTR PHS 2006-2“为急性和慢性中枢神经系统损伤的有希望的治疗方法开发新的临床前试验”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，使大约20万美国人坐在轮椅上，其中三分之二的新受害者年龄在30岁以下。脊髓损伤后的功能缺陷是由于轴突的损伤或断裂，神经元和胶质细胞的损失，以及脱髓鞘。脊髓损伤的病理不仅由最初的机械损伤决定，还由缺血、自由基形成、炎症和兴奋毒性等继发过程决定。目前，SCI还没有治愈的方法，甲基强的松龙是临床唯一的选择，即使没有FDA的批准。显然，迫切需要新的治疗方法来最大限度地减少灾难性的后果，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来源于载脂蛋白E （apoE）的受体结合区。我们的深入研究表明，小apoe模拟物在消除脊髓损伤的继发性损伤和促进脊髓损伤恢复方面具有显著的生物活性，其可能途径是：(1)抗炎症；(2)减少过量的Ca2+内流，防止谷氨酸的兴奋性毒性；(3)减少自由基和一氧化氮的产生；(4)促进髓鞘碎片的清除，髓鞘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。我们的初步数据显示，COG133对已建立的多发性硬化症和创伤性脑损伤小鼠模型具有神经保护作用，这些损伤性疾病与SCI有许多共同特征。我们假设COG133可能代表了新一代的脊髓损伤治疗，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，在这个I期提案中，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期研究的完成将决定COG133是否是脊髓损伤的候选疗法。脊髓损伤（SCI）是一种主要的破坏性创伤性中枢神经系统疾病，使大约20万美国人坐在轮椅上，其中三分之二的新受害者年龄在30岁以下。由于甲强的松龙是临床疗效可疑的唯一选择，严重未满足脊髓损伤治疗的需要。现在，我们提出了一种从载脂蛋白E （apoE）中提取的小合成肽，即COG133，作为一种有希望的治疗SCI的候选药物。COG133的设计和合成是基于我们对apoE的神经生物学作用的深入研究。我们的初步探索表明，COG133可能通过多种机制在脊髓损伤后的继发性损伤中发挥神经保护作用，并可能直接促进轴突再生，从而促进功能恢复。在本一期研究中，我们将首先在脊髓损伤小鼠压缩模型中测试其潜在的神经保护作用。本研究的完成可能验证COG133是否是一种有前景的脊髓损伤治疗方法。

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.