Nonlipogenic ABCA1 inducers for ADRD

ADRD 的非脂肪生成 ABCA1 诱导剂

• 批准号: 10651799
• 负责人: Gregory R. J Thatcher
• 金额: $ 75.55万
• 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/10651799
• 关键词: ABCB1 gene; ADD-1 protein; 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; Body Weight decreased; Brain; Cell Culture Techniques; Cell Line; Cells; Cholesterol; Chronic; Cognition; Data; Dementia; Dependence; Development; Disease associated microglia; Dose; Dyslipidemias; 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; Macrophage; Measures; Metabolic Diseases; Modeling; Mus; Mutation; Neurons; Neutropenia; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Oral; Oral Administration; PPAR gamma; Pathogenicity; Pathology; Pharmacodynamics; Pharmacology; Phenotype; Prevalence; Primary carcinoma of the liver cells; Primates; Reporter; Reporting; Research; Risk; Risk Factors; Safety; Series; Steatohepatitis; Testing; Triglycerides; Up-Regulation; Validation; Weight Gain; aging population; antagonist; apolipoprotein E-3; 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; meetings; metabolome; metabolomics; mouse model; neural; neuropathology; new therapeutic target; obesogenic; patient population; pharmacodynamic model; promoter; 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 FAD小鼠模型中的ABCA1加剧了病理学，行为定义；和罕见的人类功能丧失 ABCA1中的突变增加了ADRD风险。 ABCA1是肝X受体（LXR）的基因产物；但是，归纳 LXR激动剂在肝脏中的脂肪生成（脂肪变性和甘油三酸酯升高）妨碍了进步。一个 非基质的ABCA1诱导剂（NLAI）将解决T2D和ADRD中的多个因果因素，包括APOE4 AD风险。我们已经为NLAI优化了一种表型药物发现策略，产生了热门系列，以增强 胆固醇动员，减弱炎症和改善的葡萄糖代谢生物标志物。一个命中和 源自IT的早期铅（CL2-57），ABCA1和APOE的增加，而无需上调脂肪生成基因。 Cl2- 57在高脂饮食（HFD）模型中口服的肥胖T2D，减弱胰岛素抵抗，降低 体重增加，并且来自全代谢组分析改善了生物标志物和脂质谱。目标1：优化NLAIS。 表型优化将由记者测定（CCF细胞中ABCA1诱导，效果最小）驱动 在HEPG2细胞中的SREBP1C上）和在CL2-57开发中验证的测试漏斗中的次级测定。 在硅和体外预测指标中，口服/脑生物利用度和SAR将指导优化。验证 PCR/免疫测定将延伸至细胞培养物中的ABCG1/APOE和FAS/SCD1。目标2：体内PK/PD和安全性。 Nlai对小鼠的治疗3天±LPS足以评估目标参与和药效学 具有安全读数的肝脏和大脑（无甘油三酸酯升高或中性粒细胞减少症）适合定义PK/PD和 给药。 AIM 3：将在5xFAD小鼠（Aβ，认知和疾病相关的5xFAD小鼠中测量体内效率a） 小胶质细胞）和b）在HFD处理的小鼠（WT，HAPOE3-KI和HAPOE4-KI）中识别特定于APOE基因型 与星形胶质细胞和神经元中体内的HFD和NLAI治疗相互作用。这些鼠标模型 将确定Nlai发展铅的效率。 AIM 4：Pretox和目标反卷积将用于 确定CYP责任和任何将为未来安全药理学提供信息的非目标。以下里程碑 提出：＃1铅Nlai在体外与脑生物利用度相遇； ＃2口头生物利用的铅Nlai 在没有脂肪生成，甘油三酸酯或中部减少症的情况下显示剂量依赖性靶标参与。 ＃3提名开发潜在客户，该铅符合体内TPP，并具有有关目标和CYP的数据。