Preclinical analysis of ischemic optic nerve treatment

缺血性视神经治疗的临床前分析

• 批准号: 8138465
• 负责人: STEVEN L BERNSTEIN
• 金额: $ 47.31万
• 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/8138465
• 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（由申请人提供）：非动脉炎性前部缺血性视神经病变 (NAION) 是一种视神经 (ON) 中风，也是突发性视神经相关视力丧失的最常见原因。 NAION 每年影响超过 6000 名美国人，通常是双侧的，目前尚无有效的治疗方法。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在生理和病理上与 NAION 非常相似的适当动物模型，这将允许测试相关治疗方法以转化为人类状况。我现在已经生成了一个非动脉炎前叶的旧世界灵长类动物模型缺血性视神经病变（pNAION）。我的初步数据显示 pNAION 和人类 NAION 之间高度相似。当前提案的一大优点是我能够使用定义明确的模型系统（从啮齿类动物到旧世界灵长类动物）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。我为该提案组建了一支非常有能力、高度专注、综合和敬业的团队。我的初步数据显示，啮齿类动物视神经梗塞后激活非动脉炎性前部缺血性视神经病变 (NAION) (PGD2) 代谢途径可减少视神经水肿并改善视网膜神经节细胞 (RGC) 的长期存活。该途径从啮齿动物到人类高度保守。最近的轶事研究还报告称，NAION 患者在使用其他减轻组织水肿的药物治疗后，临床功能得到改善。我假设，通过减少 pNAION 的早期视神经水肿，我可以改善梗死后 RGC 的存活率和视神经功能。这项转化研究将确定 PGD2 激活和 ON 水肿减轻是否可能成为 NAION 的有效神经保护治疗方法。共有三个子目标：表征视网膜和视神经功能的早期变化以及最终神经元损失和组织重塑，以确定早期干预和最大恢复的适当间隔。 b.确定早期水肿减轻是否可以改善中风后视神经功能。我将激活 PGD2 通路以减少 pNAION 引起的 ON 水肿，并使用高分辨率光学相干断层扫描 (OCT)、电生理学技术和磁共振 (MR) 成像评估 ON 功能。体内结果将与组织病理学和免疫化学结果相关。 c.将 PGD2 激活与目前用于减少临床 NAION 诱导的 ON 水肿的 VEGF 阻断药物进行比较，以证实减少水肿方法的潜在临床有效性。公共卫生相关性：非动脉炎性视神经 (ON) 中风 (NAION) 目前每年影响超过 6000 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非人类灵长类动物 NAION 模型，并确定了有效治疗啮齿动物 ON 中风的保守途径。该提案将确定通过激活该通路，并另外使用市售药物减少中风后视神经肿胀，我们是否可以改善中风后视神经功能并加速梗死后的恢复。