Novel Restorative Therapy for Spinal Cord Injury

描述（由申请人提供）：脊髓损伤的新型恢复性疗法脊髓损伤（SCI）是一种毁灭性的创伤性中枢神经系统疾病，约有253,000名美国人严重致残，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损伤或轴突切断、神经元和胶质细胞丧失以及脱髓鞘。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，而且缺乏FDA的批准。显然，迫切需要新的治疗方法，以最大限度地减少灾难性后果，更有效地改善脊髓损伤后的神经功能。Cognosci开发了COG系列抗炎/神经保护肽，这些肽来源于载脂蛋白E （apoE）的受体结合区。我们的I期研究证实了我们的亲本肽COG133在人类脊髓损伤小鼠模型中显著促进功能恢复并减少组织病理病变大小。我们超越了我们的目标，发现COG化合物既具有神经保护作用，又具有神经修复作用，似乎可以促进髓鞘再生。我们的深入研究表明，apoe - COG肽在消除脊髓损伤的继发性损伤和促进脊髓损伤恢复方面发挥着重要的生物活性，其可能途径是：(1)抗炎症；(2)抗兴奋毒性和减少细胞内Ca2+超载；(3)减少自由基和一氧化氮的产生；(4)促进髓磷脂重建，保护少突胶质细胞。这个二期项目将利用我们之前的成功工作，通过比较三种更有效和更像药物的COG化合物在两种已建立的SCI模型中的治疗效果，确定急性SCI的药物先导。此外，我们将开始有限的临床前安全性和毒性研究，并计划在未来的II期继续拨款中完成整个安全性和毒性分析，这是FDA在进行人体临床试验之前进行IND申请的要求。公共卫生相关性：这项II期研究的完成将使我们能够选择一种用于治疗急性脊髓损伤的主要候选药物，并进行fda要求的安全性/毒性分析。为了填补严重未满足的脊髓损伤治疗需求，COG化合物可能代表新一代的恢复性脊髓损伤治疗药物，具有减少继发性损伤的神经退行性变和重建受损轴突和髓鞘的双重潜力。考虑到脊髓损伤的衰弱性、患者群体的规模和惊人的医疗成本，目前开发一种新的脊髓损伤治疗方法的项目对脊髓损伤患者及其家属具有重大的个人、社会和经济效益。

DESCRIPTION (provided by applicant): Novel Restorative Therapy for Spinal Cord Injury Spinal cord injury (SCI) is a devastating traumatic CNS disorder that significantly disables about 253,000 Americans where two-thirds of the new victims are under the age of 30. Functional deficits following SCI result from damage to axons or severance cutting 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 in the clinic, and it lacks FDA approval. Clearly, novel therapies are urgently needed to maximally reduce the disastrous outcome and more effectively improve neurological functions following SCI. Cognosci has developed the COG series of anti-inflammatory/neuroprotective peptides, which are derived from the receptor-binding region of apolipoprotein E (apoE). Our Phase I study established proof-of-principle that our parent peptide, COG133, significantly promoted functional recovery and decreased histopathological lesion size in a mouse model of compressive injury of human SCI. We exceeded our aims by finding that COG compounds are both neuroprotective and neurorestorative and appear to be promoting remyelination. Our intensive studies revealed that apoE-based COG peptides exert significant bioactivities relevant to eliminate the secondary damage and foster the recovery of SCI in the following possible pathways: (1) anti-inflammation; (2) anti-excitotoxicity and reducing intracellular Ca2+ overload; (3) reducing the production of free radical species and nitric oxide; (4) promoting the reconstruction of myelin and protecting oligodendrocytes. This Phase II proposal will capitalize on the success of our previous work to identify the drug lead for acute SCI by comparison of therapeutic efficacy of three more potent and more drug-like COG compounds in two established models of SCI. Furthermore, we will start the limited preclinical safety and toxicity studies with the identified lead compound in this grant and are planning to complete the entire safety and toxicity profiling in a future Phase II continuation grant, which is required by the FDA for an IND application before proceeding to the human clinical trials. PUBLIC HEALTH RELEVANCE: The completion of this Phase II study will enable us to select one lead candidate for the treatment of acute SCI and to proceed to FDA-required safety/toxicity profiling. To fill the critically unmet need for SCI therapy, COG compounds may represent a new generation of restorative SCI therapeutics with the dual potentials of diminishing neurodegeneration of secondary damage and rebuilding damaged axon and myelin. Considering the debilitating nature of SCI, size of the patient population, and the startling healthcare costs, the current project to develop a novel therapy for SCI has significant personal, social, and economic benefit to SCI victims and their families.