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

项目摘要 神经炎症，以小胶质细胞活化和促炎细胞因子增加为特征 在阿尔茨海默病（AD）的早期就很明显，并且似乎在疾病中起重要作用。 进展通过TREM2（髓样细胞上表达的触发受体2）的信号传导介导了这一过程。 通过对小胶质细胞活化的影响来调节炎症反应。TREM2也被认为是一种风险 基因中存在错义突变的AD因子与AD风险增加相关， 脑脊液中TREM2水平与疾病严重程度降低相关。令人兴奋的是，TREM2是 我们的研究小组成员最近表明，新设计的口服药物是一个可药用的目标， 特工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， 在神经炎症和认知障碍也很明显的模型中，它还没有被开发用于 使用AD。本文提出的研究将开始填补Sob临床前试验中的这些现有空白， AM2。 在目标1中，我们将优化引起TREM2最大增加所需的口服Sob-AM 2浓度 在大脑中表达而不引起毒性。目标2和3将利用确定的剂量，确定 在AD小鼠模型中确定治疗开始的最佳时间并评估疗效。Aim 2将使用5xFAD模型 而Aim 3将使用tau蛋白病的PS19模型来研究β-淀粉样蛋白积累的影响， 口服Sob-AM 2治疗的早期与晚期开始对TREM2活化对AD的下游作用 病理学以及神经变性、认知和神经炎症。我们亦会监察 甲状腺激素信号传导的下游靶点，以鉴定Sob-AM2的非TREM2相关作用，以及 以确保没有异常信号传导的证据并且没有观察到外周脱靶效应。 这项工作将解决围绕第一种口服活性物质的剂量和治疗持续时间的关键问题， 靶向TREM2的小分子药物。鉴于缺乏疾病修饰AD疗法，Sob-AM2是一种非常有效的治疗方法。 开发用于AD的有前景的候选药物并完成这些基本的临床前研究 在这个项目中描述的将大大加快其最终的临床转化。

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.