Nonlipogenic ABCA1 inducers for ADRD - Supplement

ADRD 的非脂肪生成 ABCA1 诱导剂 - 补充品

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos 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

项目摘要

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.

阿尔茨海默氏病和相关痴呆症（ADRD）构成了日益严重的健康危机。同样，慢性代谢由于肥胖症患病率和其他风险，诸如2型糖尿病（T2D）之类的疾病正在增加因素。 T2D是ADRD的危险因素，T2D和ADRD共享共同的因果机制：胰岛素反抗;葡萄糖代谢受损；炎;血脂异常；胆固醇动员受损。这 APOE4等位基因是AD的最大遗传危险因素。 APOE4的脂质较差，并且需要脂质为了稳定性和正功能，由ATP结合盒转运蛋白ABCA1控制。删除家庭AD（FAD）小鼠模型中的ABCA1加剧了病理学，行为定义；和罕见的人类损失 - ABCA1的功能突变增加了ADRD风险。 ABCA1是肝X受体（LXR）的基因产物；但是，LXR激动剂诱导肝脏中脂肪生成（脂肪变性和甘油三酸酯升高）已阻碍进步。非脂肪性ABCA1诱导剂（NLAI）将解决T2D和ADRD中的多个因果因素，在AD中包括APOE4风险。我们已经优化了针对NLAI的表型药物发现策略，产生了命中增强胆固醇动员，减弱炎症和改善葡萄糖生物标志物的系列代谢。一击和早期的领先优势（CL2-57），增加了ABCA1和APOE，没有上调脂肪生成基因。 CL2-57在高脂饮食（HFD）模型中口服肥胖T2D，减弱胰岛素抵抗，体重增加降低，并且来自全代谢组分析改善了生物标志物和脂质轮廓。父级U01的目的是使用表型和其他验证的测定法优化NLAI CL2-57的发展。在计算机和体外预测指标中，口服/脑生物利用度和SAR将引导优化。口头和脑生物利用度是2年级进展的标准，在第4年的研究中候选者计划在AD的动物模型中：A）在5xFAD小鼠（Aβ，认知和疾病相关的小胶质细胞）中 b）在HFD处理的小鼠（WT，HAPOE3-KI和HAPOE4-KI）中识别APOE基因型特定相互作用进行HFD和Nlai治疗。 CL3-3是从CL2-57开发的，具有提高的ABCA1诱导效力胆固醇动员。尽管CL3-3不符合大脑的生物利用度标准，但它是在一项在E3/4FAD小鼠的试验研究中测试（5xFAD小鼠与Hapoe3/Hapoe4-Tr小鼠在实验室中与HAPOE3/HAPOE4-TR小鼠交叉。已故的玛丽·乔·拉杜（Mary Jo Ladu 脂肪生成。拟议的补充剂将支持5xFAD和HAPOE-KI小鼠中CL3-3的严格探索定义了该nlai与FAD发病机理和HAPOE的相互作用。这项工作将加速进步朝向Nlai候选药物。