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.

项目概要 阿尔茨海默病 (AD) 是退伍军人事务部 (VA) 中最常诊断出的痴呆症类型 医疗系统。目前尚无治疗方法可以减缓或阻止 AD 的神经退行性过程。 我的研究项目一直致力于开发可用于 IND 的 AD 新型治疗策略。 我们专注于研究一种改善认知功能的新靶点，称为 synaptojanin 1 (synj1) 和几株产品线 我的研究小组和其他人的数据表明 Synj1 减少对 AD 的有益作用是。 大脑和突触中主要的磷酸肌醇二磷酸 (PIP2) 降解酶 synj1 增加。 表达和活动与 AD 的认知衰退和病理过程有关，例如 早期内涵体的增大和 ApoE4 诱导的认知缺陷是由 synj1 多态性确定的。 在早发型和晚发型家族性 AD 受试者中，这种现象与发病年龄和 synj1 表达增加有关 与认知缺陷和位置细胞功能障碍相关。此外，不溶性 synj1 增加并且 在 AD 人脑中积聚在斑块相关的营养不良性神经突和神经原纤维缠结周围， 尤其是在 APOE4+ AD 大脑中，synj1 的基因敲除可减轻 AD 相关的病理变化， 具体来说，synj1 的下调与 PIP2 水平升高可预防寡聚抗体。 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。 synj1的部分敲低可逆转ApoE4诱导的溶酶体缺陷并改善ApoE4的行为缺陷 基因敲入小鼠模型，以及家族性 AD (FAD) 和唐氏综合症的多种动物模型。 synj1 的调节还可挽救轻度创伤性脑损伤 (mTBI) 引起的 PIP2 失调并预防 最近，我们收集的数据表明 synj1 还原的作用。 这些研究共同证明了调节 AD 中小胶质细胞功能和神经炎症的有益作用。 synj1 减少对 AD 的影响我们一直在开发具有 synj1 降低作用的新型小分子支架。 能力并确定了 FDA 批准的药物（尼莫地平），该药物可降低 Synj1 蛋白和 Aβ 水平 在短期治疗中，它还改善了 AD 小鼠模型的认知功能。 长期服用尼莫地平未能降低大脑 Aβ42 水平（特别是不溶性部分），或 然后我们利用药物化学开发了尼莫地平结构类似物。 增强其 synj1 降低作用（靶向作用）并降低其钙通道活性（脱靶作用）的方法 两种尼莫地平衍生物：SynaptoCpd #9 和 Cpd #6 从命中到先导中选择。 筛选和先导化合物优化，表现出改善的口服生物利用度和增加的长期体内功效 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 （VA Tech Transfer 提交的 PCT/US2018/062020）这些发现奠定了基础。 使用 synj1 降低药物治疗 AD 的概念验证 (PoC) 该项目的目标是执行以下任务。 两种先导化合物的 IND 授权研究，用于准备 IND 申请和 I 期临床试验 我们将： 1) 对 SynaptoCpd #9 和 Cpd #6 进行体外 ADME 和体内 DMPK 研究（目标 1）； 其次是 2) 药效学研究（急性剂量范围发现和慢性疗效研究）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 #9 和 Cpd #6（目标 3），使用之前储存的来自经 SynaptoCpd #9 和 Cpd 处理的小鼠的血浆样本 #6（预防和治疗范例），以及从 DMPK 研究中收集的新样本 （目标 1）和 PD/毒性研究（目标 2）。本申请的目标旨在促进下一步 IND 申请。 最终目标是过渡到临床研究并将我们的新型 AD 疗法商业化。