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.

项目摘要目前针对阿尔茨海默病 (AD) 的可用治疗方法仅能适度改善认知能力最近针对淀粉样蛋白-β (Aβ) 产生或清除的临床试验并未显示。疗效促使人们重新审视 AD 患者的大脑。显示出神经酰胺的积累，神经酰胺是一种信号分子，也是外泌体的组成部分神经酰胺的主要来源之一是通过中性催化的鞘磷脂水解。鞘磷脂酶 2 (nSmase2) 即使神经酰胺通过 nSMase2 短暂增加。上调是正常大脑功能的一部分，实验证据表明慢性 nSMase2 上调会导致负面影响，包括神经炎症和氧化应激。还表明 nSMase2 通过外泌体分泌参与 Aβ 聚集和 tau 蛋白传播此外，通过遗传或药理学抑制外泌体合成。抑制 nSMAse2 显着降低体外和体内 Aβ 聚集和 tau 增殖从而为 AD 治疗开辟了一条新途径，而 nSmase2 正在成为 AD 领域的重要参与者。病因学方面，目前的 nSMase2 抑制剂不足以开发潜在的治疗方法。目前可用的抑制剂具有局限性，包括效力低（IC50 为 µM 水平）、溶解度差和有限的大脑渗透性为了解决这些限制，我们开发了人类 nSMase2 高值。通量筛选分析并筛选了超过 350,000 种化合物，从而鉴定出属于不同化学系列的几个命中结果对其中两个来自不同化学系列的命中结果进行了早期优化。化学系列产生了两种有效的化合物，IC50 分别为 50 和 300 nM。被证实为外泌体释放抑制剂并表现出良好的药代动力学特征和脑渗透率（AUCbrain/AUCplasma = 0.27 和 0.6）。该提案的目标是进一步优化这些。 nSMase2 抑制剂可识别有效的、选择性的、可穿透大脑的候选药物以进行概念验证在未来的 IND 启用研究之前以及最终针对 AD 患者的治疗，目标 1 是进行。旨在提高效力的结构-活性关系研究目标 2 是表征目标化合物。 1 用于外泌体释放的功能性抑制、代谢稳定性、选择性和体内药代动力学。目标 3 是通过评估 3xTg 小鼠中选定的化合物来进行体内概念验证研究所提出的工作涉及一个新的治疗靶点，该靶点在机械上与 AD 不同。先前在 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药物样 nSMase2 抑制剂。