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。由于肥胖和其他风险的普遍存在，2 型糖尿病 (T2D) 等疾病正在增加 T2D 是 ADRD 的危险因素，并且 T2D 和 ADRD 具有共同的因果机制：胰岛素。抵抗力；葡萄糖代谢受损；炎症；血脂异常； APOE4 等位基因是 AD 的最大遗传风险因素，ApoE4 脂化不良，需要对 apoE 进行脂化。为了实现稳定性和积极功能，由 ATP 结合盒转运蛋白 ABCA1 的删除控制。家族性 AD (FAD) 小鼠模型中的 ABCA1 会恶化病理和行为缺陷，并导致罕见的人类损失 ABCA1 的功能突变会增加 ADRD 风险。ABCA1 是肝脏 X 受体 (LXR) 的基因产物；然而，LXR 激动剂诱导肝脏中的脂肪生成（脂肪变性和甘油三酯升高）阻碍了非脂肪生成 ABCA1 诱导剂（NLAI）将解决 T2D 和 ADRD 的多种致病因素，包括 AD 中的 APOE4 风险，我们优化了 NLAI 的表型药物发现策略，取得了成功。增强胆固醇动员、减轻炎症和改善葡萄糖生物标志物的系列一次打击和由此产生的早期先导 (CL2-57)，增加了 ABCA1 和 APOE，但没有。在肥胖 T2D 模型中口服上调脂肪生成基因 CL2-57，减弱胰岛素抵抗，减少体重增加，并且通过全面的代谢组学分析改善生物标志物和亲本 U01 的目标是使用表型和其他经过验证的测定来优化 NLAI。 CL2-57 的口服/大脑生物利用度和 SAR 的计算机模拟和体外预测因子的开发将提供指导。口服和大脑生物利用度是先导药物第 2 年和第 4 年研究进展的标准。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） B) 在 HFD 治疗的小鼠（WT、hAPOE3-KI 和 hAPOE4-KI）中鉴定 APOE 基因型特异性相互作用采用 HFD 和 NLAI 治疗的 CL3-3 是从 CL2-57 开发而来，具有改进的 ABCA1 诱导效力。尽管 CL3-3 不符合进展的大脑生物利用度标准，但它是有效的。在 E3/4FAD 小鼠（5xFAD 小鼠与 hAPOE3/hAPOE4-TR 小鼠在实验室中杂交）的初步研究中进行了测试已故的 Mary Jo Ladu）证明了 AD 生物标志物的改善和大脑 ABCA1 的增加，而没有外周血拟议的补充剂将支持 5xFAD 和 hAPOE-KI 小鼠中 CL3-3 的严格探索。确定 NLAI 与 FAD 发病机制和 hAPOE 的相互作用，这项工作将加速进展。 NLAI 候选药物。