Novel Disease-modifying Small Molecules for Treatment of Alzheimer's Disease”

用于治疗阿尔茨海默病的新型疾病修饰小分子 –

• 批准号: 10485602
• 负责人: Dongming Cai
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485602
• 关键词: Abeta clearance; Acceleration; Acute; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease therapy; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Attenuated; Behavior; Behavioral; Binding Proteins; Biological Availability; Biological Markers; Blood - brain barrier anatomy; Brain; Calcium Channel; Canis familiaris; Cells; Chemistry; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cognitive deficits; Collaborations; Data; Defect; Dementia; Development; Diagnosis; Disease; Dose; Down Syndrome; Down-Regulation; Drug Kinetics; Early Endosome; Ensure; Enzymes; Evaluation; Exhibits; Foundations; Functional disorder; Funding; Future; Genetic; Genetic Polymorphism; Goals; Human; Impaired cognition; In Vitro; Investigational Drugs; Investigational New Drug Application; Knock-in Mouse; Lead; Legal patent; Marketing; Medical; MicroRNAs; Mission; Morbidity - disease rate; Mus; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurofibrillary Tangles; Nimodipine; Oral; Parents; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Phospholipids; Plasma; Preparation; Preventive; Process; Proteins; Rattus; Research; Role; SYNJ1 gene; Sampling; Sensitivity and Specificity; Serum; Surrogate Markers; Synapses; System; Therapeutic; Toxic effect; Toxicology; Traumatic Brain Injury; United States Department of Veterans Affairs; United States Food and Drug Administration; Veterans; analog; apolipoprotein E-4; biomarker development; chronic traumatic encephalopathy; cognitive function; cognitive performance; commercialization; drug development; drug metabolism; efficacious treatment; efficacy study; exosome; familial Alzheimer disease; genotoxicity; human disease; hyperphosphorylated tau; improved; in vivo; innovation; interest; knock-down; lead optimization; manufacture; mild traumatic brain injury; mortality; mouse model; neuroinflammation; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; potential biomarker; pre-clinical; preclinical development; prevent; programs; protein metabolite; scaffold; screening; side effect; small molecule; success; tau Proteins

PROJECT SUMMARY Alzheimer's disease (AD) is the most frequently diagnosed type of dementia within the Veterans Affairs (VA) Medical System. Currently no treatment is available to slow down or stop neurodegenerative processes of AD. My research program has an ongoing interest of developing IND-enabling novel therapeutic strategies for AD. We focus on studying a novel target to improve cognitive function, called synaptojanin 1 (synj1) and several lines of data from my research group as well as others suggest beneficial effects of synj1 reduction in AD. Synj1 is the main phosphoinositol bisphosphate (PIP2) degrading enzyme in the brain and synapses. Increased synj1 expression and activities have been associated with cognitive decline and pathological processes of AD, such as enlargement of early endosomes and ApoE4-induced cognitive deficits. The synj1 polymorphisms identified in early- and late-onset familial AD subjects are associated with age of onset, and increased synj1 expression correlates with cognitive deficits and place cell dysfunction. In addition, insoluble synj1 is increased and accumulated around plaque-associated dystrophic neurites and neurofibrillary tangles in AD human brains, particularly in APOE4+ AD brains. Genetic knockdown of synj1 attenuates AD-related pathological changes and behavioral deficits. Specifically, down-regulation of synj1 with elevated PIP2 levels protect against oligomer Ab- induced toxic effects on synaptic integrity and promotes Aβ clearance through the endo-lysosomal pathway. Partial knockdown of synj1 reverses ApoE4-induced lysosomal defects and improves behavior deficits in ApoE4 knock-in mouse models, as well as multiple animal models of familial AD (FAD) and Down syndrome. Down- regulation of synj1 also rescues mild traumatic brain injury (mTBI)-induced PIP2 dysregulation and prevents development of tau hyper-phosphorylation. Recently, we have gathered data suggesting a role of synj1 reduction in modulating microglial function and neuro-inflammation in AD. Together, these studies support beneficial effects of synj1 reduction in AD. We have been developing scaffolds of novel small molecules with synj1-lowering capabilities and identified an FDA-approved drug (nimodipine) that reduces synj1 protein and Aβ levels both in vitro and in vivo. It also improved cognitive function in AD mouse models in short-term treatment. However, chronic administration of nimodipine failed to reduce brain Aβ42 levels (particularly insoluble fractions), or to improve cognitive function. We then developed nimodipine structural analogs using medicinal chemistry approaches to potentiate its synj1-lowering effects (on-target effects) and reduce its calcium channel activity (off- target side effects). Two nimodipine derivatives: SynaptoCpd #9 and Cpd #6 were selected from hit-to-lead screening and lead optimization, exhibiting improved oral bioavailability and increased long-term in vivo efficacy when compared to their parent compound nimodipine using both familial and sporadic AD mouse models (PCT/US2018/062020 filed by the VA Tech Transfer). These findings establish the foundation at the level of Proof-of-Concept (PoC) to treat AD with synj1-lowering agents. The objectives of the project are to perform the IND-enabling studies of two lead compounds in preparation of the IND application and phase I clinical trial studies. We will: 1) perform in vitro ADME and in vivo DMPK studies of SynaptoCpd #9 and Cpd #6 (Aim 1); followed by 2) pharmacodynamic studies (acute dosing range finding and chronic efficacy studies) as well as exploratory toxicity studies (Aim 2); 3) develop target engagement and surrogate biomarkers for SynaptoCpd #9 and Cpd #6 (Aim 3) using previously stored plasma samples from mice treated with SynaptoCpd #9 and Cpd #6 (preventive and therapeutic treatment paradigms), as well as new samples collected from DMPK studies (Aim 1) and PD/toxicity studies (Aim 2). The goals of this application aim to facilitate next step IND application with ultimate goals of transitioning into clinical studies and the commercialization of our novel AD therapies.

项目摘要 阿尔茨海默病（AD）是退伍军人事务部（VA）内最常见的痴呆症类型 医疗系统。目前没有治疗方法可以减缓或停止AD的神经退行性过程。 我的研究项目一直对开发IND使能的AD新治疗策略感兴趣。 我们专注于研究一种新的目标，以改善认知功能，称为synaptojanin 1（synj 1）和几个线 来自我的研究小组以及其他人的数据表明，减少synj 1对AD有益。Synj 1是 脑和突触中主要的磷酸肌醇二磷酸（PIP 2）降解酶。增加synj 1 表达和活性与AD的认知衰退和病理过程相关，例如 早期核内体增大和ApoE 4诱导的认知缺陷。synj 1基因多态性 在早发和迟发性家族性AD受试者中， 与认知缺陷和定位细胞功能障碍有关。此外，不溶性synj 1增加， 聚集在AD人脑中斑块相关的营养不良神经突和神经纤维缠结周围， 特别是在APOE 4 + AD脑中。基因敲除synj 1可减轻AD相关的病理变化， 行为缺陷具体地说，下调synj 1与升高的PIP 2水平保护免受寡聚体Ab- 诱导对突触完整性的毒性作用，并通过内-溶酶体途径促进Aβ清除。 synj 1的部分敲除逆转ApoE 4诱导的溶酶体缺陷并改善ApoE 4的行为缺陷 基因敲入小鼠模型，以及家族性AD（FAD）和唐氏综合征的多种动物模型。向下- synj 1的调节还可以挽救轻度创伤性脑损伤（mTBI）诱导的PIP 2失调并预防 tau过度磷酸化的发展。最近，我们收集的数据表明synj 1减少的作用， 在调节AD中的小胶质细胞功能和神经炎症方面。总之，这些研究支持有益的 Synj 1减少在AD中的作用。我们一直在开发新的小分子支架， 能力，并确定了一种FDA批准的药物（尼莫地平），降低synj 1蛋白和Aβ水平， 体外和体内。它还在短期治疗中改善了AD小鼠模型的认知功能。然而，在这方面， 尼莫地平长期给药不能降低脑Aβ42水平（特别是不溶性部分）， 改善认知功能。然后，我们开发了尼莫地平结构类似物使用药物化学 增强其降低SynJ 1的作用（靶向作用）和降低其钙通道活性（关闭）的方法 目标副作用）。两种尼莫地平衍生物：SynaptoCpd#9和Cpd#6选自命中-先导化合物， 筛选和先导物优化，表现出改善的口服生物利用度和增加的长期体内功效 当使用家族性和散发性AD小鼠模型与其母体化合物尼莫地平进行比较时， (PCT/US 2018/062020由VA技术转移提交）。这些发现奠定了基础， 用降低synj 1的药物治疗AD的概念验证（Proof-of-Concept，缩写为PART）。该项目的目标是执行 两种先导化合物的IND使能研究，以准备IND申请和I期临床试验 问题研究我们将：1）进行SynaptoCpd#9和Cpd#6的体外ADME和体内DMPK研究（目的1）; 其次是2）药效学研究（急性剂量范围探索和慢性疗效研究）以及 探索性毒性研究（目标2）; 3）开发SynaptoCpd的靶点参与和替代生物标志物 使用先前储存的来自用SynaptoCpd#9和Cpd#6处理的小鼠的血浆样品， #6（预防性和治疗性治疗范例），以及从DMPK研究中收集的新样本 (Aim 1）和PD/毒性研究（目的2）。本申请的目的是促进下一步IND申请 最终目标是过渡到临床研究和我们的新型AD疗法的商业化。