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 FAD小鼠模型中的ABCA 1加重病理和行为缺陷;以及罕见的人类功能丧失 ABCA 1突变增加ADRD风险。ABCA 1是肝X受体（LXR）的基因产物;然而， LXR激动剂引起的肝脏脂肪生成（脂肪变性和甘油三酯升高）的增加阻碍了进展。一 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APOE 4 AD的风险。我们优化了NLAI的表型药物发现策略，产生了增强效果的热门系列 胆固醇动员、减轻炎症和改善葡萄糖代谢的生物标志物。一个打击和 一个早期的铅衍生自它（CL 2 -57），增加ABCA 1和载脂蛋白E，没有上调脂肪基因。CL2- 57在致肥胖T2 D的高脂饮食（HFD）模型中口服给药，减弱胰岛素抵抗，降低 体重增加，并从全代谢组学分析改善生物标志物和脂质谱。目标1：优化非地方援助指标。 表型优化将由报告基因测定驱动（在CCF细胞中诱导ABCA 1，影响最小 在HepG 2细胞中的SREBP 1c上）和在CL 2 -57开发中验证的测试漏斗中的二级测定。 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。验证可 PCR/免疫测定将扩展到细胞培养物中的ABCG 1/APOE和FAS/SCD 1。目的2：体内PK/PD和安全性。 NLAI处理小鼠3天± LPS足以评估靶向接合和药效学。 肝脏和大脑的安全性读数（无甘油三酯升高，也无中性粒细胞减少）适合定义PK/PD， 剂量。目的3：将在5xFAD小鼠（Aβ、认知和疾病相关性 小胶质细胞）和B），以鉴定APOE基因型特异性 在星形胶质细胞和神经元中与HFD和NLAI治疗的体内和离体相互作用。这些小鼠模型 将建立一个NLAI开发领导的有效性。目标4：Pretox和目标去卷积将用于 确定可告知未来安全药理学的不良反应和任何脱靶。以下里程碑 提出：1号铅NLAI满足体外TPP与脑生物利用度; 2号口服生物可利用铅NLAI， 显示脑中的剂量依赖性靶点参与，而无脂肪生成、甘油三酯升高或中性粒细胞减少症; #3提名符合体内TPP的开发负责人，并提供靶点和CYP数据。