Treatment strategies for autoimmune demyelinating optic neuritis

自身免疫性脱髓鞘性视神经炎的治疗策略

• 批准号: 9249047
• 负责人: Scott M Plafker
• 金额: $ 21.44万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249047
• 关键词: Acute; Adoptive Cell Transfers; Adoptive Transfer; Animals; Antioxidants; Apoptosis; Autoimmune Process; Axon; Blindness; Cell Death; Cell Survival; Cells; Central Nervous System Diseases; Chronic; Clinical Trials; Clinical assessments; DNA; Data; Demyelinations; Disease; Employee Strikes; Experimental Autoimmune Encephalomyelitis; Experimental Models; FDA approved; Formulation; Free Radicals; Fumarates; Goals; Helper-Inducer T-Lymphocyte; Immune; Immunoglobulin G; Individual; Infiltration; Inflammation; Inflammatory; Interferon-beta; Intervention; Knowledge; Lead; Lesion; Link; Lymphocytic Infiltrate; Magnetic Resonance Imaging; Measures; Modeling; Monocular Vision; Morphology; Multiple Sclerosis; Mus; Nerve Degeneration; Neuroglia; Neuromyelitis Optica; Nitrogen; Oligodendroglia; Optic Nerve; Optic Neuritis; Oxidative Stress; Oxygen; Patients; Pharmacology; Prevention strategy; Publishing; Randomized Controlled Trials; Recurrence; Refractory; Relapse; Retinal Degeneration; Retinal Ganglion Cells; Severities; Steroid therapy; Stress; Symptoms; Testing; Therapeutic; Treatment Efficacy; Vision; Visual; Visual Acuity; aquaporin 4; base; cell type; diffusion weighted; disorder prevention; in vivo; innovation; insight; macrophage; motor deficit; mouse model; multiple sclerosis patient; nanoparticle; neurological pathology; neutrophil; novel; patient population; prevent; protein expression; public health relevance; reconstitution; retinal apoptosis; seropositive; stem; targeted treatment; therapeutic evaluation; tool; transcription factor; treatment strategy

 DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) and Neuromyelitis optica (NMO) are chronic inflammatory diseases of the central nervous system characterized by autoimmune attack of oligodendrocytes, demyelination of axons, and neurodegeneration. The two diseases share multiple symptoms, most notably a recurring optic neuritis that frequently results in monocular vision loss with MS and binocular loss with NMO. These recurring attacks can cause permanent vision loss due to apoptosis of retinal ganglion cells (RGCs), the axons of which comprise the optic nerve. The mechanisms underlying RGC death remain a major knowledge gap and as a result, there are currently no reliable treatments. Most NMO patients are seropositive for aquaporin-4 (AQP4) IgG, and multiple agents are currently being evaluated to treat AQP4-positive disease, but an estimated 12-25% of NMO patients are seronegative for AQP4. The goal of this application is to develop targeted therapeutics that mitigate optic neuritis for the susceptible MS and NMO patient populations whose disease is refractory to steroid therapy and/or is AQP4-negative. Our approach is to preserve RGC survival and vision by amplifying the capacity of RGCs and the immune cells that drive optic nerve demyelination and inflammation to neutralize free radical stress. This approach stems from the hypothesis that free radical stress is a major contributor to optic neuritis, and from our discovery that mice genetically ablated for Nrf2, the master anti-oxidant transcription factor, have an increased severity of visual deficits, RGC loss, and optic nerve inflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE). This model reconstitutes key features of the optic neuritis observed in patients with MS and NMO, and we will explore two iterations of the model. In Specific Aim 1, we will test if amplifying Nrf2 activity mitigates optic neuritis and vision loss in the Th1 adoptive transfer EAE model, which mimics MS optic neuritis. In Specific Aim 2, we will test if amplifying Nrf2 activity mitigates optic neuritis and vision loss in the Th1 adoptive transfer EAE model, which is more representative of NMO. The therapeutics to be tested are novel Nrf2-expressing DNA nanoparticles (Nrf2-DNPs) that we developed and an FDA-approved pharmacological activator of Nrf2. The therapies will be tested individually or in combination and will be investigated for their capacity to prevent the onset of optic neuritis and to block recurrent episodes following the first attack. Therapeutic efficacy will be assessed in vivo by daily optokinetic tracking (OKT) to measure visual acuity and weekly diffusion-weighted and morphological MRI to correlate OKT changes with demyelination and inflammation. Additional analyses will be done to measure how effectively the therapeutics decrease RGC loss, inflammation/demyelination of the optic nerve, infiltration of specific immune cell types, an the extent of oxidative/nitrosative damage. The proposed studies have significant potential value from a therapeutic standpoint, and will reveal mechanistic insights into the contributions of free radical stress and damage to autoimmune demyelinating optic neuritis.

 描述(申请人提供)：多发性硬化(MS)和视神经脊髓炎(NMO)是以少突胶质细胞自身免疫攻击、轴突脱髓鞘和神经变性为特征的中枢神经系统慢性炎症性疾病。这两种疾病都有多种共同的症状，最显著的是反复发作的视神经炎，经常导致MS患者的单眼视力丧失和NMO患者的双眼视力丧失。这些反复发作可导致永久性视力丧失，因为视网膜神经节细胞(RGC)的凋亡，其轴突组成视神经。RGC死亡的机制仍然是一个重大的知识空白，因此，目前还没有可靠的治疗方法。大多数NMO患者的水通道蛋白-4(AQP4)抗体血清阳性，目前正在评估多种药物治疗AQP4阳性疾病，但估计有12%-25%的NMO患者AQP4血清阴性。这项应用的目标是开发减轻视神经炎的靶向疗法。 对于疾病对类固醇治疗无效和/或AQP4阴性的MS和NMO易感人群。我们的方法是通过放大RGC和免疫细胞的能力来保护RGC的存活和视力，RGC和免疫细胞驱动视神经脱髓鞘和炎症，以中和自由基应激。这种方法源于自由基应激是视神经炎的主要诱因的假设，以及我们的发现，在实验性自身免疫性脑脊髓炎(EAE)的小鼠模型中，通过基因去除主要抗氧化剂转录因子Nrf2的小鼠有更严重的视觉缺陷、RGC丢失和视神经炎症。该模型重建了在MS和NMO患者中观察到的视神经炎的关键特征，我们将探索该模型的两次迭代。在特定的目标1中，我们将测试放大Nrf2活性是否减轻视神经炎和 模拟MS视神经炎的Th1过继转移性EAE模型中的视力损失。在具体目标2中，我们将在更具代表性的NMO的Th1过继转移性EAE模型中测试放大Nrf2活性是否减轻视神经炎和视力损失。被测试的治疗药物是我们开发的新型表达Nrf2的DNA纳米颗粒(Nrf2-DNPs)和FDA批准的Nrf2的药理激活剂。这些疗法将单独或联合进行测试，并将调查其预防视神经炎发作和阻止首次发作后复发的能力。治疗效果将通过每日视动跟踪(OKT)来测量视力和每周扩散加权和形态MRI来评估治疗效果，以将OKT的变化与脱髓鞘和炎症相关联。还将进行其他分析，以衡量这些疗法如何有效地减少RGC丢失、视神经炎症/脱髓鞘、特定免疫细胞类型的渗透，以及氧化/亚硝化损伤的程度。从治疗的角度来看，这些研究具有重要的潜在价值，并将揭示自由基应激和损伤在自身免疫性脱髓鞘视神经炎中的作用机制。