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增加为特征 产生，在阿尔茨海默病(AD)的早期就很明显，似乎在疾病中扮演着重要的角色 进步。通过TREM2(触发髓系细胞上表达的受体2)的信号介导这一过程 炎症反应通过影响小胶质细胞的激活。TREM2也被认为是一种风险 基因错义突变与AD风险增加和升高有关的AD因子 脑脊液中的TREM2水平与疾病严重程度的降低相关。令人兴奋的是，TREM2是 最近我们研究小组的成员表明，通过新设计的口服可用药，它是一个可用药靶点 代理，SOB-AM2。而SOB-AM2已被证明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也很明显的模型，它还没有被开发出来用于 在AD中使用。这里提出的研究将开始填补SOB临床前测试的这些现有空白。 AM2. 在目标1中，我们将优化口服Sob-AM2的浓度，以最大限度地增加TREM2 在大脑中表达，不会引起毒性。目标2和目标3将利用确定的剂量，确定 阿尔茨海默病小鼠模型的最佳治疗开始时间和疗效评估。AIM 2将使用5xFAD模型 而Aim 3将使用PS19的肌萎缩症模型来研究 早、晚口服SOB-AM2治疗对激活TREM2对AD下游影响的比较 病理以及神经变性、认知和神经炎症。我们还将监测 甲状腺激素信号的下游靶点以确定SOB-AM2的非TREM2相关效应以及 以确保没有异常信号的证据，也没有看到外周偏离目标的影响。 这项工作将解决围绕第一种口服活性药物的剂量和治疗持续时间的关键问题， 靶向TREM2的小分子药物。鉴于缺乏修改AD疗法的疾病，SOB-AM2是一种非常 开发用于AD的有希望的候选药物并完成这些基本的临床前研究 这个项目中描述的将大大加快其最终的临床翻译。