Evaluating a novel, orally-active TREM2-targeting drug in AD

评估一种新型口服活性 TREM2 靶向药物治疗 AD 的效果

• 批准号: 10735206
• 负责人: Nora Gray
• 金额: $ 44.38万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735206
• 关键词: Acceleration; Agonist; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amides; Amyloid beta-42; Amyloid beta-Protein; Animals; Anti-Inflammatory Agents; Antibodies; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; C57BL/6 Mouse; Central Nervous System; Cerebrospinal Fluid; Chromatography; Cognition; Demyelinations; Diet; Disease; Disease Progression; Disease model; Dose; Drug Kinetics; Drug Targeting; Drug usage; Enzyme-Linked Immunosorbent Assay; Event; Experimental Autoimmune Encephalomyelitis; Female; Gene Expression; Genes; Harvest; Human; Immunohistochemistry; Impaired cognition; Inflammatory; Inflammatory Response; Integral Membrane Protein; Late Onset Alzheimer Disease; Light; Liquid substance; Macrophage; Mass Spectrum Analysis; Mediating; Medicine; Microglia; Missense Mutation; Modeling; Monitor; Multiple Sclerosis; Mus; National Institute on Aging; Nerve Degeneration; Neurodegenerative Disorders; Oral; Parents; Pathogenesis; Pathology; Pathway interactions; Patients; Performance; Peripheral; Permeability; Phagocytosis; Pharmaceutical Preparations; Phase; Phenotype; Phosphorylation; Play; Preclinical Testing; Prodrugs; Production; Property; Proteins; Rodent Model; Role; Serum; Severity of illness; Signal Transduction; Spinal Cord Lesions; TREM2 gene; Tauopathies; Therapeutic; Therapeutic Intervention; Thyroid Hormone Receptor; Thyroid Hormones; Toxic effect; Triiodothyronine; Wild Type Mouse; Wit; Work; abeta accumulation; brain tissue; clinical translation; cognitive function; cognitive testing; comparison control; cytokine; design; dosage; drug candidate; efficacy evaluation; experimental study; glial activation; hormonal signals; improved; inflammatory marker; interest; male; member; mouse model; neurofilament; neuroinflammation; neuroprotection; new therapeutic target; novel; novel therapeutics; overexpression; pre-clinical; preclinical study; receptor; side effect; small molecule; targeted treatment; tau Proteins; transcriptome sequencing; treatment duration

Project Summary Neuroinflammation, characterized by microglial activation and increased pro-inflammatory cytokine production, is evident early in Alzheimer's disease (AD) and appears to play an important role in disease progression. Signaling through TREM2 (Triggering receptor expressed on myeloid cells 2) mediates this inflammatory response through effects on microglial activation. TREM2 has also been recognized as a risk factor for AD with missense mutations in the gene being associated with increased risk of AD and elevated levels of TREM2 in the cerebrospinal fluid correlating with decreased disease severity. Excitingly, TREM2 was recently shown by members of our study team to be a druggable target by the newly designed, orally available agent, Sob-AM2. While Sob-AM2 has shown to be neuroprotective in other neurodegenerative disease models where neuroinflammation and cognitive impairment are also evident, it has not yet been developed for use in AD. The studies proposed here will begin to fill in these existing gaps in the preclinical testing of Sob- AM2. In Aim 1 we will optimize the concentration of oral Sob-AM2 needed to elicit maximum increases in TREM2 expression in the brain without evoking toxicity. Aims 2 and 3 will utilize the identified dose, determine the optimal timing of treatment initiation and assess efficacy in AD mouse models. Aim 2 will use the 5xFAD model of beta-amyloid accumulation while Aim 3 will use the PS19 model of tauopathy to investigate the effects of an early versus late start of oral Sob-AM2 treatment on the downstream effects of TREM2 activation on AD pathology as well as neurodegeneration, cognition and neuroinflammation. We will also monitor the downstream targets of thyroid hormone signaling to identify non-TREM2 related effects of Sob-AM2 as well as to ensure that there is no evidence of aberrant signaling and that peripheral off-target effects are not seen. This work will address critical questions surrounding dosage and treatment duration of the first orally active, small molecule drug to target TREM2. Given the lack of disease modifying AD therapies, Sob-AM2 is a very promising candidate drug to develop for use in AD and completion of these essential preclinical studies described in this project will greatly accelerate its eventual clinical translation.

项目摘要 神经炎症，以小胶质细胞激活和促炎细胞因子的增加为特征 生产在阿尔茨海默氏病（AD）早期很明显，并且似乎在疾病中起重要作用 进展。通过Trem2发出信号（触发受体在髓样细胞上表达2）介导了这一点 通过对小胶质激活的影响的炎症反应。 TREM2也被认为是风险 基因中具有错义突变的AD因子与AD风险增加相关并升高 脑脊液中的TREM2水平与疾病严重程度降低相关。令人兴奋的是，Trem2是 我们研究团队的成员最近显示的是新设计的，口服可用的目标 代理，SOB-AM2。虽然SOB-AM2已显示在其他神经退行性疾病中具有神经保护作用 神经炎症和认知障碍的模型也很明显，尚未开发 在AD中使用。此处提出的研究将开始填补SOB-临床前测试中的这些现有空白。 AM2。 在AIM 1中，我们将优化trem2最大增加所需的口服SOB-AM2的浓度 在大脑中的表达而无需引起毒性。目标2和3将利用确定的剂量，确定 治疗开始的最佳时机和评估AD小鼠模型中的功效。 AIM 2将使用5XFAD模型 AIM 3的β-淀粉样蛋白积累的积累将使用Tauopathy的PS19模型来研究 口服SOB-AM2治疗对AD的下游影响的早期开始与晚期开始 病理以及神经退行性，认知和神经炎症。我们还将监视 甲状腺激素信号传导的下游靶标，以识别SOB-AM2和 为了确保没有迹象表明信号传导，并且看不到外围脱靶效应。 这项工作将解决有关剂量和治疗持续时间的关键问题， 小分子药物以靶向tREM2。鉴于缺乏修饰AD疗法的疾病，SOB-AM2非常 有希望的候选药物可以开发用于AD和完成这些基本临床前研究 该项目中描述的将极大地加速其最终的临床翻译。