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.

阿尔茨海默病和相关痴呆症（ADRD）构成了日益严重的健康危机。同样，慢性代谢 由于肥胖和其他风险的流行，2型糖尿病（T2 D）等疾病正在增加， 因素T2 D是ADRD的风险因素，T2 D和ADRD具有共同的因果机制：胰岛素 抵抗;葡萄糖代谢受损;炎症;血脂异常;和胆固醇动员受损。的 APOE 4等位基因是AD的最大遗传危险因素。ApoE 4脂化较差，需要apoE脂化 对于稳定性和正功能，由ATP结合盒转运蛋白ABCA 1控制。删除 家族性AD（FAD）小鼠模型中的ABCA 1加重了病理和行为缺陷; ABCA 1的功能突变增加ADRD风险。ABCA 1是肝X受体（LXR）的基因产物; 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）阻碍了 中求进工作总非脂肪生成ABCA 1诱导剂（NLAI）将解决T2 D和ADRD中的多种致病因素， 包括AD中的APOE 4风险。我们优化了NLAI的表型药物发现策略， 增强胆固醇动员，减轻炎症，改善葡萄糖生物标志物的系列 新陈代谢.一次击中和早期铅来自它（CL 2 -57），增加ABCA 1和APOE，而没有 上调脂肪生成基因。在致肥胖T2 D的高脂饮食（HFD）模型中口服施用CL 2 -57， 减轻胰岛素抵抗，减少体重增加，并通过全代谢组学分析改善生物标志物， 血脂谱母体U 01的目标是使用表型和其他经验证的测定优化NLAI， 开发CL 2 -57。口服/脑生物利用度和SAR的计算机模拟和体外预测因子将指导 优化.口服和脑生物利用度是电极导线研究第2年和第4年进展的标准 候选药物计划用于AD动物模型：A）5xFAD小鼠（Aβ、认知和疾病相关小胶质细胞） 和B）在HFD处理的小鼠（WT、hAPOE 3-KI和hAPOE 4-KI）中鉴定APOE基因型特异性相互作用 HFD和NLAI治疗。CL 3 -3是由CL 2 -57开发的，具有提高的ABCA 1诱导效力 和胆固醇动员。虽然CL 3 -3不符合进展的脑生物利用度标准，但它是一种有效的治疗方法。 在E3/4FAD小鼠（5xFAD小鼠与hAPOE 3/hAPOE 4-TR小鼠杂交，实验室为 晚期玛丽乔Ladu），证明AD生物标志物的改善和脑ABCA 1的增加，而没有外周 脂肪生成拟定的补充将支持在5xFAD和hAPOE-KI小鼠中对CL 3 -3进行严格探索 以确定这种NLAI与FAD发病机制和hAPOE的相互作用。这项工作将加快进展 一个NLAI候选药物。