Nonlipogenic ABCA1 inducers for ADRD - Supplement

ADRD 的非脂肪生成 ABCA1 诱导剂 - 补充品

• 批准号: 10832305
• 负责人: Gregory R. J Thatcher
• 金额: $ 37.3万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10832305
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Acceleration; Acute; Address; Age Months; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amendment; Amyloid beta-Protein; Animal Model; Animals; Apolipoprotein E; Attenuated; Behavioral; Biological Assay; Biological Availability; Biological Markers; Body Weight decreased; Brain; Cardiometabolic Disease; Cholesterol; Chronic; Clinical Trials; Cognition; Collaborations; Critical Pathways; Data; Development; Diabetes Mellitus; Disease associated microglia; Doctor of Philosophy; Dose; Dyslipidemias; Female; Funding; Genes; Genotype; Goals; Grant; Health; High Fat Diet; Human; Hypertriglyceridemia; Impairment; In Vitro; Inflammation; Insulin; Insulin Resistance; Knock-in Mouse; Lead; Link; Lipids; Liver; Liver X Receptor; Measures; Metabolic Diseases; Metformin; Methodology; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Oral Administration; Paper; Parents; Pathogenesis; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phenotype; Physiology; Pilot Projects; Plasma; Population; Precision therapeutics; Prevalence; Published Comment; Publishing; Reporting; Research; Research Proposals; Risk; Risk Factors; Risk Reduction; Selection Criteria; Series; Study models; Synapses; Testing; Tissues; Treatment Efficacy; Triglycerides; Weight Gain; Work; apolipoprotein E-3; apolipoprotein E-4; behavioral study; dementia risk; disorder risk; drug candidate; drug discovery; expectation; experimental study; familial Alzheimer disease; follow-up; gene product; genetic risk factor; glucose metabolism; healthy aging; improved; in silico; insulin signaling; lead candidate; lipid biosynthesis; loss of function mutation; male; metabolomics; mouse model; neuroinflammation; new therapeutic target; obesogenic; prototype; synaptic function; timeline

Alzheimer’s disease and related dementia (ADRD) constitutes a growing health crisis. Equally, chronic metabolic diseases such as type 2 diabetes (T2D) are increasing, because of the prevalence of obesity and other risk factors. T2D is a risk factor for ADRD and both T2D and ADRD share common causal mechanisms: insulin resistance; impaired glucose metabolism; inflammation; dyslipidemia; and impaired cholesterol mobilization. The APOE4 allele is the greatest genetic risk factor for AD. ApoE4 is poorly lipidated and lipidation of apoE, required for stability and positive function, is controlled by the ATP-binding cassette transporter ABCA1. Deletion of ABCA1 in familial AD (FAD) mouse models exacerbates pathology and behavioral deficits; and rare human loss- of-function mutations in ABCA1 increase ADRD risk. ABCA1 is a gene product of liver X receptor (LXR); however, induction of lipogenesis in the liver (steatosis and triglyceride elevation) by LXR agonists has hindered progress. A nonlipogenic ABCA1-inducer (NLAI) would address multiple causal factors in T2D and ADRD, including APOE4 risk in AD. We have optimized a phenotypic drug discovery strategy for NLAIs, yielding hit series that enhanced cholesterol mobilization, attenuated inflammation, and improved biomarkers of glucose metabolism. One hit and an early lead derived from it (CL2-57), increased ABCA1 and APOE, without upregulating lipogenic genes. CL2-57 administered orally in the high-fat diet (HFD) model of obesogenic T2D, attenuated insulin resistance, reduced weight gain, and from full metabolomic analysis improved biomarkers and lipid profiles. The goal of the parent U01 is to optimize NLAIs using phenotypic and other assays validated in development of CL2-57. In silico and in vitro predictors of oral/brain bioavailability and SAR will guide optimization. Oral and brain bioavailability are criteria for progression in Year 2 and in Year 4 study of a lead candidate is planned in animal models of AD: A) in 5xFAD mice (Aβ, cognition, and disease-associated microglia) and B) in HFD-treated mice (WT, hAPOE3-KI, and hAPOE4-KI) to identify APOE genotype specific interactions with HFD and NLAI treatment. CL3-3 was developed from CL2-57 with improved potency for ABCA1 induction and cholesterol mobilization. Although CL3-3 does not meet brain bioavailability criteria for progression, it was tested in a pilot study in E3/4FAD mice (5xFAD mice crossed with hAPOE3/hAPOE4-TR mice in the lab of the late Mary Jo Ladu) demonstrating improvement of AD biomarkers and increased brain ABCA1 without peripheral lipogenesis. The proposed supplement will support rigorous exploration of CL3-3 in 5xFAD and hAPOE-KI mice to define the interactions of this NLAI with FAD pathogenesis and hAPOE. This work would accelerate progress towards a an NLAI drug candidate.

阿尔茨海默病及相关痴呆症(ADRD)构成日益严重的健康危机。同样，慢性新陈代谢 由于肥胖和其他风险的流行，2型糖尿病(T2D)等疾病正在增加 各种因素。T2D是ADRD的危险因素，T2D和ADRD都有共同的致病机制：胰岛素 抵抗力；糖代谢受损；炎症；血脂异常；以及胆固醇动员受损。这个 ApoE4等位基因是AD的最大遗传危险因素。载脂蛋白E4脂化不良，需要脂化载脂蛋白E 对于稳定性和正功能，是由ATP结合盒转运体ABCA1控制的。删除 家族性AD(FAD)小鼠模型中的ABCA1加剧了病理和行为缺陷；罕见的人类损失- ABCA1功能缺失突变增加ADRD风险。ABCA1是肝X受体(LXR)基因产物； 然而，LXR激动剂诱导肝脏脂肪生成(脂肪变性和甘油三酯升高)已受到阻碍。 进步。非生脂ABCA1诱导物(NLAI)将解决T2D和ADRD中的多种原因， 包括AD中的APOE4风险。我们已经优化了NLAI的表型药物发现策略，产生了HIT 增强胆固醇动员、减轻炎症和改善葡萄糖生物标记物的系列药物 新陈代谢。一次命中和由此产生的早期领先(CL2-57)，增加了ABCA1和APOE，没有 上调生脂基因。Cl2-57在高脂饮食(HFD)肥胖T2D模型中灌胃， 减轻胰岛素抵抗，减少体重增加，从完全代谢分析中改善生物标记物和 血脂谱。母公司U01的目标是使用表型和其他经过验证的分析来优化NLAI CL2-57的研制在硅胶和体外中，口服/脑生物利用度和SAR的预测指标将指导 优化。口服和脑生物利用度是铅研究第二年和第四年进展的标准 候选的AD动物模型：A)在5xFAD小鼠中(Aβ、认知和疾病相关的小胶质细胞) 和B)在HFD处理的小鼠中(WT、hAPOE3-Ki和hAPOE4-Ki)，以确定APOE基因特异性的相互作用 接受HFD和NLAI治疗。CL3-3是在CL2-57的基础上发展而来的，具有更强的ABCA1诱导效力 和胆固醇动员。尽管CL3-3不符合进展的大脑生物利用度标准，但它 在E3/4FAD小鼠(5xFAD小鼠与hAPOE3/hAPOE4-tr小鼠在 已故的Mary Jo Ladu)显示AD生物标志物的改善和脑ABCA1的增加，而不使用外周设备 脂肪生成作用。建议的补充将支持在5xFAD和hAPOE-Ki小鼠中对CL3-3进行严格的探索 明确这种NLAI与FAD发病机制和hAPOE的相互作用。这项工作将加快进度 一名NLAI药物候选人。