TDP-43 aggregation inhibitors for the treatment of ALS
用于治疗 ALS 的 TDP-43 聚集抑制剂
基本信息
- 批准号:9047209
- 负责人:
- 金额:$ 49.96万
- 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:2015-09-15 至 2017-03-14
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAmyotrophic Lateral SclerosisAnimal ModelAreaBiochemicalBiologicalBiological MarkersBloodBlood - brain barrier anatomyBostonBrainCell DeathCell modelCell physiologyCellsCellular StressCerebrospinal FluidCharacteristicsChestChronicCollaborationsCytoplasmCytoplasmic GranulesDataDiagnosisDiseaseDisease ProgressionDoctor of PhilosophyDoseDrug KineticsExhibitsFaceFamilial Amyotrophic Lateral SclerosisFamilyFunctional disorderGenesGoalsHalf-LifeHumanImmunohistochemistryIn VitroIndividualInheritedInhibitory Concentration 50Injection of therapeutic agentLaboratoriesLeadLegLicensingLifeLinkMass Spectrum AnalysisMeasuresMedicalMessenger RNAModelingModificationMolecular WeightMusMuscleMutationNeurodegenerative DisordersNeuronsNuclearPathogenesisPathologyPathway interactionsPatientsPenetrancePenetrationPharmacologic SubstancePhasePhosphorylationPhosphorylation SiteProcessProteinsRNARNA-Binding ProteinsResearchRespiratory DiaphragmRoleSiteSkeletal MuscleSmall Business Innovation Research GrantSpinal CordStagingStatistical Data InterpretationStressSurfaceTechnologyTestingTherapeuticTimeTransgenic AnimalsTransgenic MiceUbiquitinationUniversitiesWestern BlottingWorkagedarmbasedaltondesigndriving forcedrug developmenteffective therapyhigh throughput screeningimprovedin vivoinhibitor/antagonistinnovationintravenous administrationmedical schoolsmouse modelmutantnervous system disordernovelnovel therapeutic interventionpreventprogramsprotein TDP-43protein aggregateprotein aggregationprotein complexpublic health relevancescaffoldsmall moleculesuccess
项目摘要
DESCRIPTION (provided by applicant): There is currently no therapy for Amyotrophic Lateral Sclerosis (ALS), which is a universally fatal neurodegenerative disease that afflicts over 1 out of
every 10,000 individuals. Protein aggregation has been implicated as a primary driving force in ALS and multiple other neurodegenerative illnesses. TDP-43 is the principle component of the protein aggregates in ALS, and mutations in TDP-43 are sufficient to cause disease in patients. There are families that have autosomally dominant inherited mutations in TDP-43 that cause ALS with 100% penetrance. This places TDP-43, along with other genetically defined mutant genes, in the cell death pathway. TDP-43 also stands out as the only one of these genetically defined ALS mutant genes that is ALSO the hallmark pathology of sporadic ALS. This is why TDP-43 is so important. TDP-43 is a RNA binding protein that is nuclear under basal conditions but translocates to the cytoplasm during stress where it forms cytoplasmic RNA/protein complexes termed "stress granules" (SGs). Disease-linked mutations in TDP-43 enhance the ability of TDP-43 to aggregate and form SGs in vitro and in animal models. Cytoplasmic TDP-43 aggregates accumulate and also co-localize with SGs in the spinal cord and brain of patients with ALS, as well as in cellular and animal models of ALS. These integrated observations all point to a strong biological connection between TDP-43, the associated SGs, and pathogenesis of ALS. The strong role of TPD-43 in the pathophysiology of ALS points to TDP-43 as a cogent pharmacological target for disease modification. Aquinnah Pharmaceuticals has licensed 10 lead compounds that inhibit TDP-43 and SG aggregation that were identified in a high throughput screen performed in the laboratory of Dr. Benjamin Wolozin (Boston University School of Medicine). In this Phase I SBIR, we propose to demonstrate the feasibility of targeting TDP-43 with these lead compounds for the treatment of ALS. The goal of this proposal is to identify two lead compounds that exhibit the best brain pharmacokinetics (penetration and half-life), and then to test the ability of the compounds to improve TDP-43 biomarkers in vivo using a transgenic mouse model of TDP-43 of ALS. In Aim 1, we will characterize the general ADME characteristics for each compound, and then investigate the pharmacokinetics in the brain to determine brain penetration and half-life for each of the lead compounds. In Aim 2, we will select the two best compounds, and test them in a pathological TDP-43 mouse model of ALS in collaboration with Dr. Wolozin. We will use acute dosing of these compounds to show biochemical benefit by assessing biomarkers of potential efficacy including TDP-43 aggregation, phosphorylation, and ubiquitination. Success in this Phase I SBIR will result in the identification
of 1-2 compounds that enter the CNS and inhibit TDP-43 aggregation in an acute dosing animal model of ALS. This will then allow a more robust drug development program to ensue, including setting the stage for chronic dosing to test the ability of these compounds to delay disease progression in vivo in SBIR Phase II.
描述(由申请人提供):目前尚无针对肌萎缩侧索硬化症 (ALS) 的治疗方法,这是一种普遍致命的神经退行性疾病,超过三分之一的患者患有该病。
每 10,000 人。蛋白质聚集被认为是 ALS 和多种其他神经退行性疾病的主要驱动力。 TDP-43 是 ALS 中蛋白质聚集体的主要成分,TDP-43 的突变足以导致患者患病。有些家族的 TDP-43 具有常染色体显性遗传突变,导致 ALS 外显率达 100%。这将 TDP-43 与其他基因定义的突变基因一起置于细胞死亡途径中。 TDP-43 也是这些基因定义的 ALS 突变基因中唯一的一个,它也是散发性 ALS 的标志性病理学。这就是 TDP-43 如此重要的原因。 TDP-43 是一种 RNA 结合蛋白,在基础条件下为细胞核,但在应激期间易位至细胞质,形成细胞质 RNA/蛋白质复合物,称为“应激颗粒”(SG)。 TDP-43 中与疾病相关的突变增强了 TDP-43 在体外和动物模型中聚集和形成 SG 的能力。在 ALS 患者的脊髓和大脑以及 ALS 的细胞和动物模型中,细胞质 TDP-43 聚集体会积累并与 SG 共定位。这些综合观察结果都表明 TDP-43、相关 SG 和 ALS 发病机制之间存在密切的生物学联系。 TPD-43 在 ALS 病理生理学中的强大作用表明 TDP-43 作为疾病缓解的有效药理学靶点。 Aquinnah Pharmaceuticals 已获得 10 种抑制 TDP-43 和 SG 聚集的先导化合物的许可,这些化合物是在 Benjamin Wolozin 博士(波士顿大学医学院)实验室进行的高通量筛选中鉴定出来的。在此 I 期 SBIR 中,我们建议证明用这些先导化合物靶向 TDP-43 治疗 ALS 的可行性。该提案的目标是确定两种表现出最佳脑药代动力学(渗透和半衰期)的先导化合物,然后使用 ALS 的 TDP-43 转基因小鼠模型测试这些化合物在体内改善 TDP-43 生物标志物的能力。在目标 1 中,我们将表征每种化合物的一般 ADME 特征,然后研究大脑中的药代动力学,以确定每种先导化合物的脑渗透和半衰期。在目标 2 中,我们将选择两种最佳化合物,并与 Wolozin 博士合作在 ALS 病理性 TDP-43 小鼠模型中进行测试。我们将使用这些化合物的急性给药,通过评估潜在功效的生物标志物(包括 TDP-43 聚集、磷酸化和泛素化)来显示生化益处。第一阶段 SBIR 的成功将导致鉴定
1-2 种化合物在 ALS 急性给药动物模型中进入 CNS 并抑制 TDP-43 聚集。这将使更强大的药物开发计划得以实施,包括为长期给药奠定基础,以测试这些化合物在 SBIR II 期体内延缓疾病进展的能力。
项目成果
期刊论文数量(0)
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Glenn Larsen其他文献
Glenn Larsen的其他文献
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Targeting tau for the development of novel Alzheimer's disease therapeutics
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10010108 - 财政年份:2018
- 资助金额:
$ 49.96万 - 项目类别:
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