Nonlipogenic ABCA1 inducers for ADRD - Supplement

ADRD 的非脂肪生成 ABCA1 诱导剂 - 补充品

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

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.

阿尔茨海默病和相关痴呆（ADRD）构成了日益严重的健康危机。同样，慢性代谢