Modulation of FcRn: A strategy to prevent autoantibody-mediated nerve injury
FcRn 的调节:预防自身抗体介导的神经损伤的策略
基本信息
- 批准号:8684787
- 负责人:
- 金额:$ 19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-01 至 2016-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffinityAnimal ModelAnimalsAntibodiesAntigen TargetingAntigen-Antibody ComplexApplications GrantsAreaArthritisAutoantibodiesAutoimmune DiseasesAutoimmune ProcessAutoimmune ResponsesAxonBindingBlood-Nerve BarrierCell surfaceClinicalClinical TrialsClinical Trials DesignComplementDataDevelopmentDiseaseDisease modelEngineeringEnhancing AntibodiesEthicsFutureGangliosidesGlycosphingolipidsGrantGuillain-Barré SyndromeHalf-LifeHumanIgG ReceptorsIgG1ImmuneImmune systemImmunoglobulin GImmunotherapyInflammationInjuryIntravenous ImmunoglobulinsLeftMeasuresMediatingModalityModelingMusMyasthenia GravisNatural regenerationNeonatalNerve CrushNerve FibersNeurologicNeuromyelitis OpticaNeuropathyParalysedPathogenicityPathologyPatientsPeripheral NervesPharmaceutical PreparationsPhasePoliomyelitisPolysaccharidesPre-Clinical ModelPropertyPublishingRanvier&aposs NodesRecoveryResearchRoleScheduleSialic AcidsSurfaceSyndromeTestingTherapeuticTherapy EvaluationTransgenic MiceUp-RegulationVariantWalkingantibody engineeringaxon regenerationbasecomparative efficacydesigninjuredneonatal Fc receptornerve injurynovel therapeuticspreventpublic health relevancerandomized placebo controlled trialrepairedresearch studysynergismtranslational approachtreatment strategyward
项目摘要
Abstract
With the near-eradication of polio, Guillain-Barr¿ syndrome (GBS) has become the most frequent cause of
acute flaccid paralysis. Current immunomodulatory treatments are only effective in a proportion of patients. For
example IVIG-a first line treatment modality in GBS-hasten recovery in only ~50% of those treated with this
medication. Despite availability of current of immunotherapies, a significant proportion of patients are left with
severe and permanent neurologic sequelae, including inability to walk independently. There is a dire need for
newer/additional treatments that can limit the axonal damage during the acute phase of the disease and
enhance repair during recovery period are desirable. For over last 20 years no new treatments have entered
the clinical arena of GBS. It is in this context we want to test an Abdeg (Fc-engineered antibody that enhance
IgG degradation by blocking neonatal Fc receptor (FcRn)) appropriate for human use as autoAb-specific
immunotherapy in preclinical models of GBS. Anti-ganglioside antibodies (Abs) are the most frequently
recognized autoimmune responses in GBS. We focus on anti-glycan Ab associated disease models in this
grant as substantial experimental data support the primary pathogenic role of these autoAbs in GBS
particularly in its axonal variants. Our group has developed two different passive transfer animal models with
anti-glycan Abs, which will be used in the proposed studies. Our preliminary studies show that mice lacking
neonatal Fc receptor (FcRn) are not susceptible to anti-ganglioside Ab-mediated nerve injury due to rapid
clearance of these Abs in an animal model. Based on these observations we postulate that Abdegs would be
protective in our animal models of anti-ganglioside Ab-mediated nerve injury. This hypothesis will be tested by
the following specific aims: Aim 1 will examine the efficacy of Abdeg (MST-HN) in animal studies by measuring
the circulating half-life of pathogenic experimental and human anti-glycan Abs and correlate this with their
pathogenic effects on intact and injured axons; Aim 2 will compare efficacy and/or synergism of IVIG with
Abdeg MST-HN in suppressing anti-glycan Ab-mediated nerve injury in animal models. For translational
purposes it would be important to determine in preclinical models whether a): Abdeg (MST-HN) and IVIG do
not have antagonistic effects; and b) these two medications have synergistic effects. Both these issues are
relevant from ethical and trial design perspective if this therapy were to extend to human studies. This project
may help in developing new treatment stratgies aiming to expedite clearnce of autoAbs and has relevance not
only to GBS but other neuroimmunological disorders including myasthenia gravis and neuromyelitis optica.
摘要
随着脊髓灰质炎的几乎根除,格林-巴利综合征(GBS)已成为脊髓灰质炎最常见的病因。
急性弛缓性麻痹目前的免疫调节治疗仅对一部分患者有效。为
实施例IVIG-GBS的一线治疗方式-仅约50%的接受该治疗的患者加速恢复
药尽管目前的免疫疗法是可用的,但仍有相当一部分患者留下了免疫缺陷。
严重和永久性神经系统后遗症,包括无法独立行走。迫切需要
更新/额外的治疗,可以限制疾病急性期的轴突损伤,
希望在恢复期间加强修复。在过去的20年里,没有新的治疗方法进入
GBS的临床竞技场。正是在这种情况下,我们想要测试一种Abdeg(Fc工程化抗体,其增强免疫原性)。
通过阻断新生儿Fc受体(FcRn)降解IgG),适用于人用作autoAb特异性抗体
GBS临床前模型的免疫治疗。抗神经节苷脂抗体(Abs)是最常见的
GBS中的自身免疫反应。我们专注于抗聚糖抗体相关的疾病模型,
大量的实验数据支持这些自身抗体在GBS中的主要致病作用
特别是在其轴突变体中。本课题组建立了两种不同的被动转移动物模型,
抗聚糖抗体,将用于拟定研究。我们的初步研究表明,
新生儿Fc受体(FcRn)对抗神经节苷脂Ab介导的神经损伤不敏感,
这些抗体在动物模型中的清除。根据这些观察,我们假设阿布德格斯
在我们的抗神经节苷脂Ab介导的神经损伤的动物模型中具有保护作用。这一假设将由以下人员进行检验:
以下具体目标:目标1将通过测量Abdeg(MST-HN)在动物研究中的功效,
病原性实验性和人抗聚糖Ab的循环半衰期,并将其与
对完整和受损轴突的致病作用;目的2将比较IVIG与
Abdeg MST-HN在动物模型中抑制抗聚糖Ab介导的神经损伤。用于平移
在临床前模型中确定a):Abdeg(MST-HN)和IVIG是否
不具有拮抗作用;和B)这两种药物具有协同作用。这两个问题都是
从伦理和试验设计的角度来看,如果这种疗法扩展到人体研究,则具有相关性。这个项目
可能有助于开发新的治疗策略,旨在加快自身抗体的清除,
也可用于其他神经免疫疾病,包括重症肌无力和视神经肌无力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
KAZIM A SHEIKH其他文献
KAZIM A SHEIKH的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('KAZIM A SHEIKH', 18)}}的其他基金
Blockade of colony stimulating factor 1 receptor to reduce inflammatory nerve injury
阻断集落刺激因子 1 受体以减少炎症神经损伤
- 批准号:
10195632 - 财政年份:2021
- 资助金额:
$ 19万 - 项目类别:
Modulation of FcRn: A strategy to prevent autoantibody-mediated nerve injury
FcRn 的调节:预防自身抗体介导的神经损伤的策略
- 批准号:
8806622 - 财政年份:2014
- 资助金额:
$ 19万 - 项目类别:
Non-Invasive Imaging to Quantify Peripheral Nerve Injury and Repair in Clinic
无创成像在临床上量化周围神经损伤和修复
- 批准号:
8446439 - 财政年份:2011
- 资助金额:
$ 19万 - 项目类别:
Non-Invasive Imaging to Quantify Peripheral Nerve Injury and Repair in Clinic
无创成像在临床上量化周围神经损伤和修复
- 批准号:
8245788 - 财政年份:2011
- 资助金额:
$ 19万 - 项目类别:
Non-Invasive Imaging to Quantify Peripheral Nerve Injury and Repair in Clinic
无创成像在临床上量化周围神经损伤和修复
- 批准号:
8106764 - 财政年份:2011
- 资助金额:
$ 19万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
Continuing Grant