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：
8049576
负责人：
FENG-QIAO LI
金额：
$ 69.56万
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 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8049576
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 Health Care Costs Horns Human Impairment Individual Inflammation Inflammatory Response Injury Investigational Drugs Investigational New Drug Application Investments Ischemia Lactated Ringer&apos s Solution 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 preclinical toxicity prevent psychologic 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.

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。目前，无法治愈SCI，而甲基丙糖酮是诊所中唯一的选择，并且缺乏FDA批准。显然，迫切需要新的疗法来最大程度地减少灾难性结果，并在SCI后更有效地改善神经功能。 Cognosci开发了一系列抗炎/神经保护肽的COG系列，该肽源自载脂蛋白E（APOE）的受体结合区域（APOE）。我们的I阶段研究确定了原理证明，我们的母肽COG133显着促进了功能恢复，并且在人类SCI的抗压损伤的小鼠模型中，组织病变大小降低。我们通过发现COG化合物既是神经保护作用又是神经训练的，并且似乎正在促进再生。我们的密集研究表明，基于APOE的COG肽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）抗脱毒性和减少细胞内Ca2+过载；（3）减少自由基物种和一氧化氮的产生；（4）促进髓磷脂的重建并保护少突胶质细胞。这项II期提案将利用我们以前的工作的成功，以比较在两个既定的SCI模型中，将三种有效和类似药物的齿轮化合物的治疗功效进行比较。此外，我们将使用该赠款中确定的铅化合物开始有限的临床前安全性和毒性研究，并计划在未来的II期持续拨款中完成整个安全性和毒性分析，FDA需要在进行人类临床试验之前进行IND应用。公共卫生相关性：这项II阶段研究的完成将使我们能够选择一名急性SCI治疗的主要候选人，并继续进行FDA要求的安全/毒性分析。为了满足对SCI治疗的急需需求，COG化合物可以代表新一代的恢复性SCI疗法，具有减少次生损伤神经变性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，患者人群的规模以及令人震惊的医疗保健成本，当前为SCI开发新疗法的项目对SCI受害者及其家人具有巨大的个人，社会和经济利益。