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

基本信息

  • 批准号:
    9249047
  • 负责人:
  • 金额:
    $ 21.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

 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(由适用提供):多发性硬化症(MS)和神经肌炎Optica(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自身免疫性攻击,轴突脱髓鞘和神经变性。这两种疾病共有多种症状,最著名的是一种反复出现的视神经神经毒素,经常导致MS和NMO双目损失导致单眼视力丧失。这些反复出现的攻击可能导致残留神经节细胞(RGC)凋亡引起的永久视力丧失,轴突包含视神经。 RGC死亡的基础机制仍然是一个主要的知识差距,因此目前尚无可靠的治疗方法。大多数NMO患者对Aquaporin-4(AQP4)IgG的血清阳性患者目前被评估以治疗AQP4阳性疾病,但估计有12-25%的NMO患者的AQP4血清负责。该应用的目的是开发靶向疗法来减轻视神经神经毒性 对于易感性疾病的易感MS和NMO患者人群,对类固醇治疗和/或AQP4阴性具有难治性。我们的方法是通过扩增RGC和驱动视神经脱髓鞘和炎症的免疫细胞的能力来保持RGC的存活和视力,从而维护RGC的生存和视力。这种方法从假设自由根本性压力是视神经神经毒性的主要原因,并且从我们发现的发现,遗传上的小鼠在NRF2(主要的抗氧化剂转录因子)中具有增加视觉缺乏的严重程度,RGC丧失和光神经丧失和光神经损失的实验性excemune Encephalsomeelision(eae exceplymyelision(eae excepphalsomeelitis)(eae exceplymyelyss)(eae exceplymyselysiss)。该模型重构在MS和NMO患者中观察到的视神经神经的关键特征,我们将探索该模型的两个迭代。在特定目标1中,我们将测试放大NRF2活性减轻视神经炎和 Th1自适应转移EAE模型中的视力丧失,该模型模仿了MS Optic Neurotis。在特定的目标2中,我们将测试在Th1自适应转移EAE模型中放大NRF2活性减轻视神经神经和视力丧失,该模型更像是NMO。要测试的理论是我们开发的新型NRF2表达DNA纳米颗粒(NRF2-DNP)和FDA批准的NRF2的药物激活剂。疗法将进行单独或组合测试,并将研究其防止视神经神经毒性发作并阻止第一次攻击后经常发作的能力进行研究。治疗有效性将通过每日光动力学跟踪(OKT)在体内进行评估,以测量视力和每周扩散加权和形态学MRI,以将OKT的变化与脱髓鞘和炎症相关。将进行其他分析,以衡量如何有效地降低RGC损失,视神经注射/脱髓鞘,特定免疫细胞类型的浸润,这是氧化/硝化损伤的程度。从治疗的角度来看,拟议的研究具有显着的潜在价值,并将揭示对自由基应力和对自身免疫性脱髓鞘神经神经的损害的贡献的机理见解。

项目成果

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Scott M Plafker其他文献

Scott M Plafker的其他文献

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{{ truncateString('Scott M Plafker', 18)}}的其他基金

Interrogating the intersection between diet and ocular autoimmunity
探究饮食与眼部自身免疫之间的交叉点
  • 批准号:
    10419170
  • 财政年份:
    2022
  • 资助金额:
    $ 21.44万
  • 项目类别:
Interrogating the intersection between diet and ocular autoimmunity
探究饮食与眼部自身免疫之间的交叉点
  • 批准号:
    10597231
  • 财政年份:
    2022
  • 资助金额:
    $ 21.44万
  • 项目类别:
OKHSC COBRE: THE ROLE OF THE UBIQUITIN SYSTEM IN RETINAL DEGENERATION
OKHSC COBRE:泛素系统在视网膜变性中的作用
  • 批准号:
    8360280
  • 财政年份:
    2011
  • 资助金额:
    $ 21.44万
  • 项目类别:
Control of redox regulators by the ubiquitin system
泛素系统对氧化还原调节剂的控制
  • 批准号:
    8727042
  • 财政年份:
    2011
  • 资助金额:
    $ 21.44万
  • 项目类别:
Control of redox regulators by the ubiquitin system
泛素系统对氧化还原调节剂的控制
  • 批准号:
    8536839
  • 财政年份:
    2011
  • 资助金额:
    $ 21.44万
  • 项目类别:
Control of redox regulators by the ubiquitin system
泛素系统对氧化还原调节剂的控制
  • 批准号:
    8106682
  • 财政年份:
    2011
  • 资助金额:
    $ 21.44万
  • 项目类别:
Control of redox regulators by the ubiquitin system
泛素系统对氧化还原调节剂的控制
  • 批准号:
    8320952
  • 财政年份:
    2011
  • 资助金额:
    $ 21.44万
  • 项目类别:
OKHSC COBRE: PROTECTING THE RETINA FROM OXIDATIVE STRESS
OKHSC COBRE:保护视网膜免受氧化应激
  • 批准号:
    8167973
  • 财政年份:
    2010
  • 资助金额:
    $ 21.44万
  • 项目类别:
OKHSC COBRE: UBIQUITIN IN HYPERGLYCEMIA-INDUCED MESANGIAL CELL HYPERTROPHY
OKHSC COBRE:泛素在高血糖引起的系膜细胞肥大中的作用
  • 批准号:
    7959775
  • 财政年份:
    2009
  • 资助金额:
    $ 21.44万
  • 项目类别:
OKHSC COBRE: UBIQUITIN IN HYPERGLYCEMIA-INDUCED MESANGIAL CELL HYPERTROPHY
OKHSC COBRE:泛素在高血糖引起的系膜细胞肥大中的作用
  • 批准号:
    7721020
  • 财政年份:
    2008
  • 资助金额:
    $ 21.44万
  • 项目类别:

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