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 阿尔茨海默氏病（AD）是退伍军人事务中最常见的痴呆症类型（VA） 医疗系统。目前尚无治疗方法可以减慢或停止AD的神经退行性过程。 我的研究计划持续不断开发针对AD的新型治疗策略。 我们专注于研究一个新的目标以改善认知功能，称为Synaptojanin 1（Synj1）和几行 我的研究小组的数据以及其他数据表明，Synj1减少AD的有益影响。 Synj1是 主磷酸肌醇双磷酸（PIP2）在大脑和突触中降解酶。 Synj1增加 表达和活动与AD的认知下降和病理过程有关 作为早期内体和APOE4诱导的认知缺陷的扩展。鉴定的Synj1多态性 在早期和晚期的家族性AD受试者中，Synj1表达与发病年龄有关 与认知定义并放置细胞功能障碍相关。此外，不溶性synj1增加了，并且 围绕与斑块相关的营养不良神经运动和神经纤维缠结在AD人类大脑中 特别是在apoe4+广告大脑中。 Synj1的遗传敲低会减弱与广告相关的病理变化和 行为定义。具体而言，synj1的下调PIP2水平升高可预防寡聚物AB- 诱导对合成完整性的毒性作用，并通过内部溶酶体途径促进Aβ清除率。 Synj1的部分敲低逆转APOE4诱导的溶酶体缺陷并改善行为定义APOE4 敲入小鼠模型，以及多种家庭AD（FAD）和唐氏综合症的动物模型。向下- Synj1的调节还反应轻度的脑损伤（MTBI）诱导的PIP2失调，并防止 tau高磷酸化的发展。最近，我们收集的数据表明了Synj1降低的作用 在调节AD中的小胶质功能和神经炎症时。这些研究共同支持有益 Synj1降低AD的影响。我们一直在开发带有Synj1降低的新型小分子的支架 能力并鉴定出FDA批准的药物（nimodipine），该药物降低了Synj1蛋白和Aβ水平都在 体内和体内。在短期治疗中，它还改善了AD小鼠模型中的认知功能。然而， 长期给药氮氨基胺无法降低大脑Aβ42水平（部分不溶部分）或 提高认知功能。然后，我们使用药物化学开发了Nimodipine的结构类似物 潜在潜在其降低降低效应（靶向效应）并减少其钙通道活性的方法（OFF- 目标副作用）。两种Nimodipine衍生物：SynaptOCPD＃9和CPD＃6从命中至领导中选择 筛选和铅优化，表现出改善的口服生物利用度，并提高体内效率 与他们的母体化合物Nimodipine相比，使用家族和零星的AD鼠标模型 （PCT/US2018/062020由VA Tech传输提交）。这些发现确定了基础 概念证明（POC）用降低的降低剂治疗AD。项目的对象是执行 针对IND应用和I期临床试验制备两种铅化合物的辅助研究 研究。我们将：1）对SynaptOCPD＃9和CPD＃6进行体外ADME和体内DMPK研究（AIM 1）； 其次是2）药学研究（急性给药范围发现和慢性有效性研究）以及 探索性毒性研究（AIM 2）； 3）SynaptOCPD的开发目标参与和替代生物标志物 ＃9和CPD＃6（AIM 3）使用先前存储的血浆样品，来自SynaptOCPD＃9和CPD的小鼠 ＃6（预防性和治疗治疗范例）以及DMPK研究收集的新样本 （AIM 1）和PD/毒性研究（AIM 2）。此应用程序的目标旨在促进下一步IND应用程序 最终的目标是过渡到临床研究和新型广告疗法的商业化。