Nonlipogenic ABCA1 inducers for ADRD

ADRD 的非脂肪生成 ABCA1 诱导剂

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' 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

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 FAD小鼠模型中的ABCA1加重了病理和行为缺陷；以及罕见的人类功能丧失 ABCA1基因突变会增加ADRD风险。ABCA1是肝X受体(LXR)的基因产物； LXR激动剂对肝脏脂肪生成(脂肪变性和甘油三酯升高)的影响阻碍了进展。一个 非致脂ABCA1诱导物(NLAI)将解决T2D和ADRD的多种原因，包括APOE4 AD的风险。我们已经为NLAI优化了表型药物发现策略，产生了增强 胆固醇动员，减轻炎症，改善葡萄糖代谢的生物标志物。一击即中 一种来自它的早期铅(CL2-57)，增加了ABCA1和APOE，但没有上调造脂基因。Cl2- 57在高脂饮食(HFD)肥胖性T2D模型中口服，减轻胰岛素抵抗，降低 体重增加，以及来自全面代谢分析的改善了生物标记物和血脂谱。目标1：优化NLAI。 表型优化将由报告分析(在CCF细胞中诱导ABCA1，影响最小)驱动 在HepG2细胞中的SREBP1c)和在CL2-57的开发中验证的测试漏斗中的二次检测。 在硅胶和体外中，口服/大脑生物利用度和SAR的预测指标将指导优化。验证者 在细胞培养中，PCR/免疫分析将扩展到Abcg1/APOE和Fas/SCD1。目的2：体内PK/PD及其安全性。 NLAI治疗小鼠3天±内毒素足以评估靶向结合和药效学 肝脏和大脑有安全读数(没有甘油三酯升高或中性粒细胞减少)，适合定义PK/PD和 给药。目的3：将在5xFAD小鼠(Aβ、认知和疾病相关)中测量体内疗效 小胶质细胞)和B)在HFD处理的小鼠(WT、hAPOE3-Ki和hAPOE4-Ki)中鉴定APOE基因特异性 HFD和NLAI治疗在星形胶质细胞和神经元体内和体外的相互作用。这些小鼠模型 将确立NLAI开发领导的效力。目标4：将使用前毒素和目标解卷积来 确定CYP的责任和任何偏离目标的情况，这将为未来的安全药理学提供信息。以下是里程碑 建议：#1铅NLAI在体外满足TPP与脑生物利用度；#2口服生物有效性铅NLAI 在没有脂肪生成、甘油三酯升高或中性粒细胞减少的情况下，表现出剂量依赖性的脑靶向参与； #3提名一位符合体内TPP的开发主管，并提供有关目标和Cyps的数据。