Preclinical analysis of ischemic optic nerve treatment

缺血性视神经治疗的临床前分析

• 批准号: 8328685
• 负责人: STEVEN L BERNSTEIN
• 金额: $ 46.7万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328685
• 关键词: Acute; Affect; American; Animal Model; Animals; Anterior Ischemic Optic Neuropathy; Biological Models; Biological Preservation; Blindness; Blood Vessels; Cell Survival; Clinical; Clinical Treatment; Clinical effectiveness; Data; Disease model; Drug usage; Early treatment; Edema; Failure; Functional disorder; Gene Expression; Grant; Health; Hemorrhage; Histologic; Human; Infarction; Institutional Review Boards; Ischemia; Ischemic Optic Neuropathy; Lesion; Magnetic Resonance Imaging; Metabolic Pathway; Modeling; Neuroprotective Agents; Optic Disk; Optic Nerve; Optical Coherence Tomography; Pathway interactions; Patients; Pharmaceutical Preparations; Primates; Probability; Prostaglandin D2; Recovery; Reducing Agents; Reporting; Resolution; Retinal; Retinal Ganglion Cells; Rodent; Rodent Model; Severities; Speed; Stroke; Swelling; Techniques; Testing; Time; Tissues; Translating; Translations; Vascular Endothelial Growth Factors; effective therapy; improved; in vivo; nervous system disorder; neuron loss; nonhuman primate; post stroke; pre-clinical; response; success; translational study; treatment trial

DESCRIPTION (provided by applicant): Nonarteritic anterior ischemic optic neuropathy (NAION) is an optic nerve (ON) stroke and the most common cause of sudden optic nerve-related vision loss. NAION affects more than 6000 Americans every year, often bilaterally, with no currently effective treatments. Every NAION clinical treatment trial has failed. A major reason for these failures is the lack of appropriate animal models closely resembling NAION physiologically and pathologically, and that would allow testing of relevant treatments for translation to the human condition.I have now generated an old-world primate model of non-arteritic anterior ischemic optic neuropathy (pNAION). My preliminary data reveal a high degree of similarity between pNAION and human NAION. A great advantage of the current proposal is my ability to test potential optic nerve stroke treatments, using well- defined model systems, from rodents through old-world primates. This will yield improved potential for clinical success. I have assembled an incredibly capable, highly focused, integrated and dedicated team for the proposal. My preliminary data reveal that activating the Nonarteritic anterior ischemic optic neuropathy (NAION) (PGD2) metabolic pathway after rodent ON infarct reduces ON edema and improves long-term retinal ganglion cell (RGC) survival. This pathway is highly conserved from rodents to humans. Recent anecdotal studies also report improved clinical function in NAION patients following treatment with other agents that reduce tissue edema. I hypothesize that, by reducing early ON edema in pNAION, I can improve post-infarct RGC survival and optic nerve function. This translational study will determine whether PGD2 activation and ON edema reduction are likely to be effective neuroprotective treatments in NAION. There are three subaims: a. Characterize early changes in retinal and optic nerve function with ultimate neuronal loss, and tissue remodeling, to determine the appropriate intervals for early intervention and maximum recovery. b. Determine if early edema reduction improves post-stroke optic nerve function. I will activate the PGD2 pathway to reduce pNAION-induced ON edema and evaluate ON function using high-resolution optical coherence tomography (OCT), electrophysiological techniques, and magnetic resonance (MR) imaging. In vivo results will be correlated with histopathologic and immunochemical findings. c. Compare PGD2 activation with currently available VEGF-blocking drugs used to reduce clinical NAION- induced ON edema, to confirm the potential clinical effectiveness of the edema-reduction approach. PUBLIC HEALTH RELEVANCE: Nonarteritic optic nerve (ON) stroke (NAION) currently affects over 6000 Americans each year. There are no effective treatments, partly because no model of the disease in a closely-related species was available for evaluating approaches that can be translated into clinical therapy. I have developed the first relevant non-human primate model of NAION, and have identified a conserved pathway effective in treating rodent ON stroke. This proposal will determine whether by activating this pathway, and additionally by reducing post-stroke ON swelling using a commercially available drug, we can improve post-ON stroke function and speed recovery after infarct.

描述(申请人提供)：非动脉炎性前部缺血性视神经病变(NAION)是一种视神经中风，是最常见的视神经相关突发性视力丧失的原因。NAION每年影响6000多名美国人，通常是双向的，目前还没有有效的治疗方法。每一次NAION临床治疗试验都失败了。这些失败的一个主要原因是缺乏合适的动物模型，在生理和病理上与NAION非常相似，这将允许测试相关的治疗方法，以便将其移植到人类条件下。我现在已经建立了一个旧世界灵长类动物非动脉炎性前部缺血性视神经病变(PNAION)模型。我的初步数据显示，pNAION和人类NAION之间有很高的相似性。当前提议的一个很大优势是，我有能力使用定义明确的模型系统，从啮齿动物到东半球灵长类动物，测试潜在的视神经中风治疗方法。这将提高临床成功的潜力。我已经为这项提案组建了一支能力超群、高度专注、全面而专注的团队。我的初步数据显示，在啮齿动物脑梗塞后激活非动脉性前部缺血性视神经病变(NAION)(PGD2)代谢途径，可以减少水肿并提高视网膜神经节细胞(RGC)的长期存活率。从啮齿动物到人类，这条途径是高度保守的。最近的轶事研究也报告了NAION患者在接受其他减轻组织水肿的药物治疗后临床功能的改善。我推测，通过减少pNAION早期的水肿，我可以改善脑梗塞后RGC的存活率和视神经功能。这项翻译研究将确定PGD2激活和减轻水肿是否可能成为NAION的有效神经保护治疗。有三个子目标：a.描述视网膜和视神经功能的早期变化与最终的神经元丢失和组织重塑，以确定早期干预和最大限度恢复的适当间隔。确定早期消肿是否能改善中风后的视神经功能。我将激活PGD2通路以减轻pNAION诱导的水肿，并使用高分辨率光学相干断层扫描(OCT)、电生理技术和磁共振(MR)成像来评估功能。体内结果将与组织病理学和免疫化学结果相关联。C.将PGD2的激活与目前用于减轻临床NAION诱导的水肿的可用的血管内皮生长因子阻断药物进行比较，以证实该消肿方法的潜在临床效果。公共卫生相关性：非动脉炎性视神经中风(NAION)目前每年影响6000多名美国人。没有有效的治疗方法，部分原因是没有密切相关物种的疾病模型可用于评估可转化为临床治疗的方法。我开发了第一个相关的NAION非人类灵长类动物模型，并确定了一种有效治疗中风啮齿动物的保守途径。这项提议将决定是否通过激活这一途径，以及通过使用商业上可用的药物减少中风后的肿胀，我们是否可以改善中风后的功能，并加快梗死后的恢复速度。