Novel Restorative Therapy for Spinal Cord Injury

脊髓损伤的新型恢复疗法

基本信息

批准号：
7822953
负责人：
FENG-QIAO LI
金额：
$ 48.19万
依托单位：
COGNOSCI, INC.
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-25 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822953
关键词：
Acute Adverse effects Affect Age American Americas Animal Model Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Area Axon Brain Budgets Cardiovascular system Cells Central Nervous System Diseases Cerebellum Cessation of life Chemistry Chronic Cicatrix Clinic Clinical Trials Contusions Corpus Callosum Cuprizone Data Demyelinations Development Dorsal Dose Economics Family Fostering Free Radical Formation Free Radicals Funding Future Generations Glutamates Goals Grant Health Care Costs Horns Human Impairment Individual Inflammation Inflammatory Response Injury Investigational Drugs Investigational New Drug Application Investments Ischemia Lactated Ringer&apos s Solution Laminectomy Lateral Lead Lesion Lipid Peroxidation Lipids Lysophosphatidylcholines Marketing Measures Mechanics Mediating Medical Methods Methylprednisolone Modeling Motor Neurons Multiple Sclerosis Mus Myelin Myelin Sheath National Institute of Neurological Disorders and Stroke Nature Nerve Nerve Degeneration Nervous System Physiology Neuroglia Neurons Nitric Oxide Nitrogen Oligodendroglia Operative Surgical Procedures Outcome Oxygen Paralysed Parents Pathogenesis Pathology Pathway interactions Patient Care Patients Peptides Performance Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Plasma Prevention Process Production Progress Reports Property Rattus Recovery Recovery of Function Rehabilitation therapy Rest Route Safety Series Slice Societies Spinal Cord Spinal cord injury Sprague-Dawley Rats Stem cells Steroids Structure Subarachnoid Hemorrhage Swelling Testing Therapeutic Time Tissues Toxic effect Traumatic Brain Injury Treatment Efficacy United States Food and Drug Administration United States National Institutes of Health Wheelchairs Work analog analytical method base cost cytokine cytotoxic disability economic cost effective therapy excitotoxicity improved intravenous injection meetings mouse model nervous system disorder neuron loss neuroprotection neurorestoration novel oxidation patient population phase 1 study phase 2 study pre-clinical preclinical safety prevent psychologic public health relevance receptor binding reconstruction restoration safety study safety testing social spinal cord compression success tissue/cell culture web site white matter

项目摘要

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.

描述（由申请人提供）：脊髓损伤的新型恢复疗法脊髓损伤 (SCI) 是一种毁灭性的创伤性中枢神经系统疾病，导致约 253,000 名美国人严重残疾，其中三分之二的新受害者年龄在 30 岁以下。 SCI 是由轴突损伤或轴突切断、神经元和神经胶质细胞丧失以及脱髓鞘引起的。 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，甲基强的松龙是临床上唯一的选择，且缺乏FDA批准。显然，迫切需要新的疗法来最大程度地减少 SCI 后的灾难性后果并更有效地改善神经功能。 Cognosci 开发了 COG 系列抗炎/神经保护肽，这些肽源自载脂蛋白 E (apoE) 的受体结合区域。我们的第一阶段研究证实了我们的母肽 COG133 在人类 SCI 压缩性损伤小鼠模型中显着促进功能恢复并减少组织病理学病变大小。我们发现 COG 化合物既具有神经保护作用又具有神经恢复作用，并且似乎可以促进髓鞘再生，从而超出了我们的目标。我们的深入研究表明，基于apoE的COG肽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)抗兴奋性毒性和降低细胞内Ca2+超载； (3)减少自由基物种和一氧化氮的产生； (4)促进髓磷脂重建，保护少突胶质细胞。这项 II 期提案将利用我们之前工作的成功，通过比较三种更有效、更类似药物的 COG 化合物在两个已建立的 SCI 模型中的治疗效果，确定急性 SCI 的先导药物。此外，我们将在本次拨款中开始对已确定的先导化合物进行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 IND 申请之前所要求的。正在进行人体临床试验。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治疗急性 SCI 的主要候选药物，并继续进行 FDA 要求的安全/毒性分析。为了满足 SCI 治疗的严重未满足的需求，COG 化合物可能代表新一代的 SCI 恢复治疗药物，具有减少继发性损伤的神经退行性变和重建受损的轴突和髓磷脂的双重潜力。考虑到 SCI 的衰弱性质、患者群体的规模以及惊人的医疗费用，当前开发 SCI 新型疗法的项目对 SCI 受害者及其家人具有重大的个人、社会和经济利益。