Regulation of Exosome Secretion as a novel therapeutic approach for Alzheimer's Disease

外泌体分泌调节作为阿尔茨海默病的新型治疗方法

基本信息

批准号：
10183123
负责人：
Barbara Stauch Slusher
金额：
$ 49.24万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183123
关键词：
3xTg-AD mouse Abeta synthesis Address Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid beta-Protein Behavioral Biochemical Biochemistry Biological Assay Brain Cells Ceramides Chemical Structure Chemicals Chemistry Chronic Clinical Clinical Trials Cognition Cognitive Cognitive deficits Collaborations Czech Republic Disease Disease Progression Drug Discovery Groups Drug Kinetics Enzymes Etiology Exhibits Future Genetic Goals Human Hydrolysis In Vitro Institutes Laboratories Link Liver Microsomes Membrane Metabolic Modeling Molecular Mus Neuroglia Neurology Neurons Oxidative Stress Patients Penetration Pharmaceutical Preparations Pharmacology Play Regulation Role Senile Plaques Series Serum Signaling Molecule Solubility Source Sphingomyelinase Sphingomyelins Structure-Activity Relationship Therapeutic Toxic effect Translational Research Up-Regulation Work abeta accumulation base drug discovery exosome follow-up high throughput screening improved in vivo inhibitor/antagonist lipid metabolism mouse model neuroinflammation new therapeutic target novel therapeutic intervention pre-clinical preclinical study prevent screening small molecule libraries tau Proteins

项目摘要

Project abstract Current available treatments for Alzheimer's disease (AD) only provide modest amelioration of cognitive and behavioral decline. Recent clinical trials targeting amyloid-β (Aβ) production or clearance did not show efficacy prompting a reexamination of approaches to AD treatment. Brains from AD patients have been shown to exhibit accumulation of ceramide, a signaling molecule and an integral component of exosomal membranes. One major source of ceramide is through the hydrolysis of sphingomyelin catalyzed by neutral sphingomyelinase 2 (nSmase2). Even though transient increases in ceramide through nSMase2 upregulation are part of normal brain functioning, experimental evidence indicates that chronic nSMase2 upregulation results in negative effects including neuroinflammation and oxidative stress. Recent studies also implicate nSMase2 in both Aβ aggregation and tau protein propagation through exosome secretion from neurons and glial cells. Moreover, inhibition of exosome synthesis by genetic or pharmacological inhibition of nSMAse2 significantly reduced Aβ aggregation and tau propagation both in vitro and in vivo thus opening a new avenue for AD therapeutics. While nSmase2 is emerging as an important player in AD etiology, the current armamentarium of nSMase2 inhibitors is inadequate to develop potential treatments. Currently available inhibitors have limitations including low potency (IC50's in µM level), poor solubility, and limited brain penetration. In order to address these limitations, we developed a human nSMase2 high throughput screening assay and screened over 350,000 compounds which led to the identification of several hits belonging to different chemical series. Early optimization of two of these hits from different chemical series led to two potent compounds with IC50s of 50 and 300 nM. Both of these compounds were confirmed as inhibitors of exosome release and exhibited good pharmacokinetic profiles and brain penetration (AUCbrain/AUCplasma = 0.27 and 0.6). The objective of this proposal is to further optimize these nSMase2 inhibitors to identify a potent, selective, brain penetrable candidate to carry out proof of concept before future IND enablement studies and ultimately for treatment of patients with AD. Aim 1 is to conduct structure-activity relationship studies to improve potency. Aim 2 is to characterize the compounds from aim 1 for functional inhibition of exosome release, metabolic stability, selectivity and in vivo pharmacokinetics. Aim 3 is to carry out in vivo proof of concept studies by evaluating selected compounds in the 3xTg mouse model of AD. The work proposed involves a novel therapeutic target which is mechanistically distinct from previous efforts in AD treatment, has the potential of addressing disease progression, and exploits two newly discovered chemical series of drug-like nSMase2 inhibitors.

项目摘要当前有关阿尔茨海默氏病（AD）的可用治疗方法仅提供对认知的适度改善和行为下降。靶向淀粉样β（Aβ）产生或清除的最新临床试验未显示功效促使重新审查AD治疗方法。广告患者的大脑已经表现出暴露于神经酰胺的积累，信号分子和外泌体的积分成分膜。神经酰胺的一个主要来源是通过中性鞘磷脂的水解鞘磷脂酶2（NSMase2）。即使通过NSMase2中的瞬时神经酰胺增加上调是正常脑功能的一部分，实验证据表明慢性NSMase2 上调导致负面影响，包括神经炎症和氧化应激。最近的研究还暗示NSMASE2通过外泌体分泌在Aβ聚集和tau蛋白传播中均暗示来自神经元和神经胶质细胞。此外，通过遗传或药理抑制外泌体合成 NSMASE2的抑制显着降低了Aβ聚集，并且体外和体内均具有tau的繁殖开辟了新的广告疗法途径。而NSMASE2正在成为广告中的重要参与者病因，NSMASE2抑制剂的当前武器库不足以开发潜在的治疗方法。目前可用的抑制剂有限制，包括低效力（µM水平IC50），溶解度差和有限的大脑穿透。为了解决这些局限性，我们开发了一个人类NSMASE2高吞吐量筛选分析并筛选了350,000多种化合物，从而确定了属于不同化学系列的几个命中。早期优化了来自不同的两次热门化学系列导致了两种潜在化合物，IC50为50和300 nm。这两种化合物都是确认为外泌体释放的抑制剂，表现出良好的药代动力学特征和大脑渗透（aucbrain/aucplasma = 0.27和0.6）。该提议的目的是进一步优化这些 NSMASE2抑制剂确定潜在的，选择性的大脑可渗透候选者，以执行概念证明在将来的IND启用研究之前，最终用于治疗AD患者。目标1是进行结构活动关系研究以提高效力。 AIM 2是表征AIM的化合物 1用于抑制外泌体释放，代谢稳定性，选择性和体内药代动力学。 AIM 3是通过评估3XTG鼠标中选定的化合物进行体内概念研究证明 AD模型。提出的工作涉及一个新型的治疗靶标，在机械上与以前在AD治疗方面的努力具有解决疾病进展的潜力，并利用了两个新发现的化学系列类似药物的NSMASE2抑制剂。