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（由申请人提供）：多发性硬化症（MS）和视神经脊髓炎（NMO）是中枢神经系统的慢性炎症性疾病，其特征是少突胶质细胞的自身免疫攻击、轴突脱髓鞘和神经变性，这两种疾病具有多种症状，最显着的是。一种复发性视神经炎，经常导致 MS 患者单眼视力丧失和 NMO 患者双眼视力丧失。这些反复发作可因细胞凋亡而导致永久性视力丧失。视网膜神经节细胞 (RGC) 的轴突构成视神经，但 RGC 死亡的机制仍然是一个主要的知识空白，因此，目前大多数 NMO 患者的水通道蛋白 4 (AQP4) 血清呈阳性。目前正在评估 IgG 和多种药物治疗 AQP4 阳性疾病，但估计 12-25% 的 NMO 患者 AQP4 血清阴性。该申请旨在开发减轻视神经炎的靶向疗法 对于类固醇治疗难治和/或 AQP4 阴性的易感 MS 和 NMO 患者群体，我们的方法是通过增强 RGC 和驱动视神经脱髓鞘和炎症的免疫细胞的能力来保护 RGC 存活和视力。这种方法源于自由基应激是视神经炎的主要原因这一假设，以及我们发现小鼠的 Nrf2（主要抗氧化剂）基因被消除的发现。转录因子，在实验性自身免疫性脑脊髓炎 (EAE) 小鼠模型中视觉缺陷、RGC 损失和视神经炎症的严重程度增加，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。探索模型的两次迭代。在具体目标 1 中，我们将测试增强 Nrf2 活性是否可以减轻视神经炎和 Th1 过继转移 EAE 模型（模拟 MS 视神经炎）中的视力丧失 在特定目标 2 中，我们将测试增强 Nrf2 活性是否可以减轻 Th1 过继转移 EAE 模型（更能代表 NMO）中的视神经炎和视力丧失。待测试的疗法是我们开发的新型表达 Nrf2 的 DNA 纳米颗粒 (Nrf2-DNP)，以及 FDA 批准的药物激活剂Nrf2.将单独或组合测试这些疗法，并研究其预防视神经炎发作和阻止首次发作后复发的能力。将通过每日光动追踪（OKT）评估体内治疗效果。测量视力和每周弥散加权和形态学 MRI，以将 OKT 变化与脱髓鞘和炎症相关联。还将进行其他分析，以测量治疗如何有效地减少 RGC 损失、炎症/脱髓鞘。视神经、特定免疫细胞类型的浸润、氧化/亚硝化损伤的程度。拟议的研究对于治疗处方具有重要的潜在价值，并将揭示自由基应激和自身免疫性脱髓鞘性视神经炎损伤的机制。 。