Nonlipogenic ABCA1 inducers for ADRD

ADRD 的非脂肪生成 ABCA1 诱导剂

基本信息

批准号：
10418342
负责人：
Gregory R. J Thatcher
金额：
$ 75.69万
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/10418342
关键词：
ABCB1 gene ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Acute Address 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 Amyloid beta-Protein Animal Model Antiinflammatory Effect Apolipoprotein E Astrocytes Astrocytoma Attenuated Behavioral Binding Biological Assay Biological Availability Biological Markers Brain Cell Culture Techniques Cell Line Cells Cholesterol Chronic Cognition Data Dementia Dependence Development Disease associated microglia Dose Dyslipidemias Fatty Liver Fluorescence Resonance Energy Transfer Future Genes Genotype Health HepG2 High Fat Diet Human Hypertriglyceridemia Immunoassay Impairment In Vitro Inflammation Inflammatory Insulin Resistance Knock-in Mouse LXRalpha protein Lead Lipids Liver Liver X Receptor Measures Metabolic Diseases Modeling Mus Mutation Neurons Neutropenia Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity Oral PPAR gamma Pathogenicity Pathology Pharmacodynamics Pharmacology Phenotype Prevalence Primary carcinoma of the liver cells Primates Proteins Reporter Reporting Research Risk Risk Factors Safety Series Steatohepatitis Testing Triglycerides Up-Regulation Validation Weight Gain aging population antagonist apolipoprotein E-4 chemoproteomics comorbidity cytokine dementia risk design drug discovery familial Alzheimer disease gene product genetic risk factor glucose metabolism improved in silico in vivo innovation insulin signaling lead optimization lipid biosynthesis lipid metabolism loss of function mutation macrophage meetings metabolome metabolomics mouse model neuropathology new therapeutic target obesogenic patient population pharmacodynamic model promoter relating to nervous system resilience screening tau Proteins

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 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. Aim 1: To optimize NLAIs. Phenotypic optimization will be driven by reporter assays (induction of ABCA1 in CCF cells, with minimal effects on SREBP1c in HepG2 cells) and secondary assays in the testing funnel validated in development of CL2-57. In silico and in vitro predictors of oral/brain bioavailability and SAR will guide optimization. Validation by PCR/immunoassay will extend to ABCG1/APOE and FAS/SCD1 in cell cultures. Aim 2: In vivo PK/PD and safety. NLAI treatment of mice for 3 days ± LPS is sufficient to assess target engagement and pharmacodynamics in the liver and brain with a safety readout (no triglyceride elevation nor neutropenia) suitable to define PK/PD and dosing. Aim 3: In vivo efficacy will be measured 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 in vivo and ex vivo in astrocytes and neurons. These mouse models will establish the efficacy of an NLAI development lead. Aim 4: Pretox and target deconvolution will be used to identify CYP liabilities and any off-targets that will inform future safety pharmacology. The following Milestones are proposed: #1 lead NLAI meeting in vitro TPP with brain bioavailability; #2 orally bioavailable lead NLAI that shows dose-dependent target engagement in the brain without lipogenesis, elevated triglycerides or neutropenia; #3 nomination of a development lead that meets the in vivo TPP with data on targets and CYPs.

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。 FAD 小鼠模型中的 ABCA1 会恶化病理和行为缺陷以及罕见的人类功能丧失； ABCA1 突变会增加 ADRD 风险；然而，ABCA1 是肝脏 X 受体 (LXR) 的基因产物。 LXR 激动剂对肝脏脂肪生成的影响（脂肪变性和甘油三酯升高）阻碍了 A 的进展。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 APOE4 我们优化了 NLAI 的表型药物发现策略，产生了增强的热门系列。胆固醇动员、减轻炎症并改善葡萄糖代谢的生物标志物。源自它的早期先导物质 (CL2-57)，增加了 ABCA1 和 APOE，但不上调 CL2- 脂肪生成基因。 57 在致肥胖 T2D 的高脂饮食 (HFD) 模型中口服给药，可减弱胰岛素抵抗，减少体重增加，并通过全面的代谢组学分析改善了生物标志物和血脂状况。目标 1：优化 NLAI。表型优化将由报告基因检测驱动（CCF 细胞中 ABCA1 的诱导，影响最小 HepG2 细胞中的 SREBP1c）和在 CL2-57 开发中验证的测试漏斗中的二次测定。口服/大脑生物利用度和 SAR 的计算机模拟和体外预测将指导优化。 PCR/免疫测定将扩展到细胞培养物中的 ABCG1/APOE 和 FAS/SCD1 目标 2：体内 PK/PD 和安全性。对小鼠进行 NLAI 治疗 3 天 ± LPS 足以评估靶点参与和药效学肝脏和大脑的安全读数（无甘油三酯升高或中性粒细胞减少）适合定义 PK/PD 和目标 3：将在 5xFAD 小鼠中测量 A) 的体内功效（Aβ、认知和疾病相关）。小胶质细胞）和 B）在 HFD 处理的小鼠（WT、hAPOE3-KI 和 hAPOE4-KI）中鉴定 APOE 基因型特异性在这些小鼠模型中，HFD 和 NLAI 治疗在体内和体外的相互作用。将确定 NLAI 开发先导的功效目标 4：Pretox 和目标反卷积将用于确定 CYP 责任和任何脱靶，为未来的安全药理学提供信息。建议：#1 先导 NLAI 与体外 TPP 和脑生物利用度相一致；#2 口服生物可利用先导 NLAI 显示大脑中剂量依赖性靶点参与，无脂肪生成、甘油三酯升高或中性粒细胞减少症； #3 提名一位开发负责人，该开发负责人的目标和 CYP 数据符合体内 TPP。