Novel Therapies for Epilepsy Using Biodegradable Immune-Modifying Nanoparticles
使用可生物降解的免疫修饰纳米颗粒治疗癫痫的新疗法
基本信息
- 批准号:9127810
- 负责人:
- 金额:$ 19.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-15 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:Activated LymphocyteAddressAdoptive TransferAdultAdverse effectsAnimal ModelAnimalsAnti-Inflammatory AgentsAnti-inflammatoryAnticonvulsantsApoptosisAstrocytesAttenuatedAutologousBiopolymersBloodBrainCellsChronicConvulsionsDataDiseaseDisease remissionDrug PrescriptionsDrug resistanceEarly treatmentEncephalitisEpilepsyEpileptogenesisEtiologyExperimental Autoimmune EncephalomyelitisFebrile ConvulsionsFeverFormulated FoodGlycolatesGlycolic-Lactic Acid PolyesterGoalsHealthHippocampus (Brain)ImmuneImmune Cell ActivationImmune responseImmunosuppressionImmunosuppressive AgentsInduced HyperthermiaInfiltrationInflammationInflammatoryInflammatory InfiltrateInfusion proceduresInjection of therapeutic agentIntravenousKainic AcidKnockout MiceLaboratoriesLeukocyte TraffickingLeukocytesLifeLinkLipopolysaccharidesMediatingMemory impairmentMicrogliaModelingMouse StrainsMultiple SclerosisMusOperative Surgical ProceduresOutcomePatientsPerformancePeripheralPlant RootsPredispositionPropertyRecurrenceRegulationRegulatory T-LymphocyteReportingResearch DesignRoleSamplingSeizuresSeveritiesSeverity of illnessSpleenStatus EpilepticusSteroidsSupplementationSymptomsTemporal Lobe EpilepsyTestingTherapeuticTransgenic MiceTranslationsUnited States Food and Drug AdministrationWorkbiodegradable polymerbrain parenchymacarboxylatecell injurycellular targetingclinical efficacyclinically relevantdesignearly childhoodearly experienceimprovedmacrophagemonocytemouse modelnanoparticleneuroinflammationneuron lossneuropathologynovelnovel therapeuticsparticlepostnatalpre-clinicalpreventprototypereceptorresearch clinical testingresponsespatial memorystandard caresuccesstraffickinguptake
项目摘要
DESCRIPTION (provided by applicant): Anticonvulsants are the standard treatment for epilepsy, but only control the symptoms without addressing the mechanisms of the disease. About 1/3 of patients develop drug-resistant epilepsies and only some are candidates for resective surgery as a final attempt to reduce seizure occurrence. Recently, our laboratory has pioneered the characterization of inflammatory cell infiltrates in surgically removed fresh brain samples in a search for novel therapies that may target the cause of epilepsy. Our data strongly indicate a role for immune cell activation in the epileptic brain irrespective of the particular etiology of epilepsy. We discovered significant brain infiltration of functionally activated lymphocytes in both epileptic patients and experimental animals. Additionally, steroids that are known for their anti-inflammatory properties have shown efficacy in a number of types of drug-resistant epilepsy. However, the profound immunosuppressive and other severe side effects of chronic steroid use have prevented widespread prescription of these drugs to otherwise treatable patients. The goal of this proposal is to use mouse models to design novel therapies to treat epilepsy using directed immunomodulatory approaches independent of broad-acting immunosuppressive agents. We propose to test the hypothesis that dampening ongoing inflammation in the brain could effectively reduce epileptogenic effects of early-life seizures and
ultimately prevent epilepsy in the absence of systemic immunosuppression. This proposal has two aims. Specific Aim 1 will determine the efficacy and underlying mechanisms by which biodegradable nanoparticles formulated from the FDA-approved biopolymer poly(lactide-co- glycolide) (PLG) induce leukocyte sequestration in the spleen and reduction of brain inflammation to prevent the priming effect of early-life seizures. Specific Aim 2 is designed to assess the efficacy of autologous natural regulatory T cell (nTreg) infusion and the potential synergistic effect of PLG nanoparticle treatment in combination with exogenously introduced nTregs in the amelioration of neuroinflammation in murine models of epilepsy. Our previous work documented the success of using biodegradable nanoparticles to treat a variety of inflammatory immune-mediated diseases in animal models. Strikingly, our preliminary results indicate that treatment with PLG nanoparticles can improve seizure outcomes in our two-hit model of epileptogenesis. We propose to elucidate the underlying therapeutic mechanisms. Additionally, we propose to test the ability of a patient's nTregs to dampen immune responses in the epileptic brain alone or in combination with PLG nanoparticles. We have previously reported that supplementation of nTregs could significantly reduce disease severity in several animal models of multiple sclerosis by preventing brain inflammation. Our approaches that target inflammation and restrict brain infiltration by inflammatory leukocyte subsets in the absence of the complicating effects of steroids are highly novel and may be a major step forward for the translation of novel treatments for the root cause of epilepsy.
描述(由申请人提供):抗惊厥药是癫痫的标准治疗方法,但只能控制症状,不能解决疾病的机制。大约1/3的患者发展为耐药性癫痫,只有一些患者适合切除手术作为减少癫痫发作的最后尝试。最近,我们的实验室率先对手术取出的新鲜脑样本中的炎性细胞浸润进行了表征,以寻找可能针对癫痫病因的新疗法。我们的数据强烈表明免疫细胞激活在癫痫脑中的作用,而不管癫痫的特定病因。我们在癫痫患者和实验动物中发现了功能活化淋巴细胞的显著脑浸润。此外,以其抗炎特性而闻名的类固醇已在许多类型的耐药性癫痫中显示出疗效。然而,长期使用类固醇的严重的免疫抑制和其他严重的副作用阻止了这些药物的广泛处方,否则可治疗的患者。该提案的目标是使用小鼠模型设计新的疗法来治疗癫痫,使用独立于广泛作用的免疫抑制剂的定向免疫调节方法。我们建议测试这一假设,即抑制大脑中正在进行的炎症可以有效地减少早期癫痫发作的致癫痫作用,
在没有全身免疫抑制的情况下最终预防癫痫。这项建议有两个目的。具体目标1将确定由FDA批准的生物聚合物聚(丙交酯-共-乙交酯)(PLG)配制的可生物降解纳米颗粒诱导脾中白细胞隔离和减少脑炎症以预防早期癫痫发作的引发效应的功效和潜在机制。具体目标2旨在评估自体天然调节性T细胞(nTreg)输注的功效以及PLG纳米颗粒治疗与外源性引入的nTreg组合在癫痫鼠模型中改善神经炎症的潜在协同作用。我们以前的工作记录了使用可生物降解的纳米颗粒在动物模型中治疗各种炎症免疫介导的疾病的成功。引人注目的是,我们的初步结果表明,在我们的癫痫发生的两次打击模型中,用PLG纳米颗粒治疗可以改善癫痫发作的结果。我们建议阐明潜在的治疗机制。此外,我们建议测试患者的nTdR单独或与PLG纳米颗粒组合抑制癫痫脑中免疫反应的能力。我们以前曾报道,在几种多发性硬化症动物模型中,通过预防脑炎症,补充nTdR可以显着降低疾病的严重程度。我们的方法针对炎症并限制炎症性白细胞亚群在没有类固醇并发症影响的情况下对大脑的浸润,这是非常新颖的,可能是针对癫痫根本原因的新型治疗方法转化的重要一步。
项目成果
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{{ truncateString('SOOKYONG KOH', 18)}}的其他基金
Novel Therapies for Epilepsy Using Biodegradable Immune-Modifying Nanoparticles
使用可生物降解的免疫修饰纳米颗粒治疗癫痫的新疗法
- 批准号:
9018306 - 财政年份:2015
- 资助金额:
$ 19.22万 - 项目类别:
Innate and Adaptive Immunity in Childhood Epilepsy
儿童癫痫的先天性和适应性免疫
- 批准号:
8843979 - 财政年份:2011
- 资助金额:
$ 19.22万 - 项目类别:
Innate and Adaptive Immunity in Childhood Epilepsy
儿童癫痫的先天性和适应性免疫
- 批准号:
8471800 - 财政年份:2011
- 资助金额:
$ 19.22万 - 项目类别:
Innate and Adaptive Immunity in Childhood Epilepsy
儿童癫痫的先天性和适应性免疫
- 批准号:
9145824 - 财政年份:2011
- 资助金额:
$ 19.22万 - 项目类别:
Innate and Adaptive Immunity in Childhood Epilepsy
儿童癫痫的先天性和适应性免疫
- 批准号:
8666078 - 财政年份:2011
- 资助金额:
$ 19.22万 - 项目类别:
Innate and Adaptive Immunity in Childhood Epilepsy
儿童癫痫的先天性和适应性免疫
- 批准号:
8087796 - 财政年份:2011
- 资助金额:
$ 19.22万 - 项目类别:
Innate and Adaptive Immunity in Childhood Epilepsy
儿童癫痫的先天性和适应性免疫
- 批准号:
8298975 - 财政年份:2011
- 资助金额:
$ 19.22万 - 项目类别:
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