Novel Combinations of Natural Product Compounds for Treatment of Alzheimer Disease and Related Dementias

用于治疗阿尔茨海默病和相关痴呆症的天然产物化合物的新组合

基本信息

批准号：
10603708
负责人：
RUI CHANG
金额：
$ 50万
依托单位：
PATH BIOTECH, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10603708
关键词：
3xTg-AD mouse Acute Address Affect Aging Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia American Amyloid beta-Protein Animal Model Animals Autopsy Biological Biological Markers Biotechnology Blood Blood specimen Brain Brain region Cells Chronic Chronic Phase Clinical Research Clinical Trials Complex Data Analyses Dementia Development Dose Drug Combinations Drug Targeting Environmental Risk Factor FDA approved Failure Female Formulation Funding Future Genetic Genetic Variation Genotype Health Care Costs Heart Human Immune response In Vitro Individual Injections Kidney Knowledge Portal Liver Measures Metabolic Microglia Multiomic Data Mus NADH National Institute on Aging Natural Compound Natural Products Neurocognitive Neurodegenerative Disorders Neurons Nicotinamide adenine dinucleotide Outcome Measure Pathway interactions Patients Performance Persons Phagocytosis Pharmaceutical Preparations Phenethyl Isothiocyanate Proteins Proteomics Publishing Regimen Research Safety Sampling Serum Sex Differences Short-Term Memory Strategic Planning Structure Synaptic Transmission Systems Biology Testing Therapeutic Therapeutic Effect Toxic effect Treatment Efficacy aged behavior test biomarker evaluation biomarker performance brain cell brain tissue cell type cognitive performance diagnostic assay dosage drug repurposing experimental study human old age (65+)human subject hyperphosphorylated tau improved in vivo in vivo Model large scale data liquid chromatography mass spectrometry male metabolomics mitochondrial metabolism morris water maze mouse model neuroinflammation neuroprotection novel novel therapeutics object recognition pre-clinical prevent protein biomarkers response screening secondary outcome sex small molecule success tau Proteins tau-1 therapeutic biomarker therapeutic development therapeutically effective therapy development transcriptome sequencing treatment duration treatment response

项目摘要

PROJECT SUMMARY/ABSTRACT In response to National Institute on Aging's (NIA) strategic plan and PAS-19-317, we propose novel therapeuticsto treat Alzheimer disease and related dementias (ADRDs). We have developed novel combinations of three natural product compounds, which modulate complementary pathways in multiple types of CNS cells (i.e., neurons, microglia) associated with AD pathology. These compounds were originally discovered through our previous computational systems biology research on AD target discovery and drug repurposing funded by NIA AMP-AD consortium where we identified over 6000 potential targets and prioritized more than 3000 candidate compounds, including natural compounds, FDA-approved drugs, and small-molecules. These compounds were identified via analysis of multi-omics data from large-scale post-mortem brain tissues of AD patients using our computational systems biology approach. In this project, we propose to further confirm the safety in wild-type (i.e., C57BL6/J mice) and therapeutic efficacy using an established murine model of AD (i.e., 3xTg mice) for our novel combinations of natural product compounds. Additionally, we will validate the correlation of our novel sex- and APOE genotype- specific serum-based metabolic biomarkers and additional protein biomarkers with the therapeutic effects of our treatment in this AD mice model. We hypothesize that these natural product combinations will prove to be safe and effective therapeutics for treatment of ADRD. To address this hypothesis, we proposed the following three aims: Aim 1: To evaluate systemic and central toxicity of NAD+/PEITC and NADH/PEITC. In this aim, we will first validate the compound structure and formulation stability with LC-MS and NMR. Next, we will use male and female C57BL6/J aged 6 months and 15 months to test brain, liver, kidney, and heart toxicity of our combinations during the acute (3 days), subacute (7 days), and chronic (28 days) periods post-dose. Aim 2: To evaluate therapeutic effects of these drug combinations on AD Biomarkers and Functional Cognitive Performance in 3xTg mice. Here, we will measure effects of our therapeutic combinations on brain levels of amyloid beta proteins (i.e., Ab(1-38), Ab(1-40), Ab(1-42)) and hyperphosphorylated tau. We will also test effects of our combinations of natural products on neurocognitive performance using the novel object recognition test and the Morris water maze. All studies in Aim 2 will be conducted in male and female 3xTg mice aged 6 months and 15 months. Aim 3: To evaluate additional blood-based therapeutic biomarkers of these drug combinations. Using blood samples collected from 15-month-old male and female 3xTg mice (Aim 2), we will validate novel blood-based metabolic and proteomics biomarkers for evaluation of therapeutic responses of our combinations via metabolomics and proteomics data analysis. Our preliminary results on both in-vitro and in-vivo model have demonstrated great promise on significant neuroprotection, stimulation of microglial phagocytosis and improving working memory of 3xTG mice. Upon the success of this project, we will be ready to further confirm the safety and therapeutic effectsof these combinations of compounds for MCI and/or very early-stage of AD in a clinical study.

项目概要/摘要为了响应国家老龄化研究所 (NIA) 的战略计划和 PAS-19-317，我们提出了新的治疗方法治疗阿尔茨海默病和相关痴呆症（ADRD）。我们开发了三种天然物质的新颖组合产品化合物，可调节多种中枢神经系统细胞（即神经元、小胶质细胞）与 AD 病理相关。这些化合物最初是通过我们之前发现的 NIA AMP-AD 资助的 AD 靶点发现和药物再利用的计算系统生物学研究我们确定了 6000 多个潜在目标并优先考虑了 3000 多种候选化合物，包括天然化合物、FDA 批准的药物和小分子。这些化合物是通过使用我们的计算技术对 AD 患者大规模死后脑组织的多组学数据进行分析系统生物学方法。在这个项目中，我们建议进一步确认野生型（即C57BL6/J）的安全性小鼠）以及使用已建立的 AD 小鼠模型（即 3xTg 小鼠）对我们的新组合的治疗效果天然产物化合物。此外，我们将验证我们的新性别和 APOE 基因型的相关性特定的基于血清的代谢生物标志物和其他蛋白质生物标志物与我们的治疗效果 AD 小鼠模型中的治疗。我们假设这些天然产品组合将被证明是安全有效的治疗方法用于治疗ADRD。为了解决这个假设，我们提出了以下三个目标：目标 1：评估 NAD+/PEITC 和 NADH/PEITC 的全身和中枢毒性。为了这个目标，我们首先使用 LC-MS 和 NMR 验证化合物结构和配方稳定性。接下来我们将使用男性和女性 C57BL6/J 6 个月和 15 个月龄，用于测试我们的组合的脑、肝、肾和心脏毒性给药后的急性期（3 天）、亚急性期（7 天）和慢性期（28 天）。目标 2：评估这些药物组合对 AD 生物标志物和功能认知的治疗效果 3xTg 小鼠的表现。在这里，我们将测量我们的治疗组合对大脑水平的影响 β 淀粉样蛋白（即 Ab(1-38)、Ab(1-40)、Ab(1-42)）和过度磷酸化 tau。我们也会测试一下效果使用新颖的物体识别测试，我们的天然产品组合对神经认知性能的影响和莫里斯水迷宫。 Aim 2 中的所有研究都将在 6 个月大的雄性和雌性 3xTg 小鼠中进行和15个月。目标 3：评估这些药物组合的其他基于血液的治疗生物标志物。使用血液从 15 个月大的雄性和雌性 3xTg 小鼠采集样本（目标 2），我们将验证新型基于血液的代谢和蛋白质组学生物标志物，用于评估我们的组合的治疗反应代谢组学和蛋白质组学数据分析。我们在体外和体内模型上的初步结果表明了在重大方面的巨大前景神经保护、刺激小胶质细胞吞噬作用和改善 3xTG 小鼠的工作记忆。于该项目的成功，我们将准备进一步确认这些组合的安全性和治疗效果临床研究中治疗 MCI 和/或极早期 AD 的化合物。