Inhibiting GPR146 in hypercholesterolemia

抑制高胆固醇血症中的 GPR146

• 批准号: 10255573
• 负责人: JAMES W LARRICK
• 金额: $ 24.97万
• 依托单位: LARIX BIOSCIENCE, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255573
• 关键词: Affinity; Aneurysm; Animal Model; Animals; Antibodies; Area; Arterial Fatty Streak; Atherosclerosis; Attenuated; Bacteriophages; Cholesterol; Cholesterol Homeostasis; Coronary heart disease; Data; Disease; Drug Kinetics; Dyslipidemias; FDA approved; Familial Hypercholesterolemia; G-Protein-Coupled Receptors; Genetic; Goals; Heart Diseases; Hepatic; Human; Knock-in; Knock-in Mouse; Knock-out; LDL Cholesterol Lipoproteins; Lesion; Libraries; Lipids; Low Density Lipoprotein Receptor; Modeling; Monoclonal Antibodies; Mus; Neurologic Deficit; Orphan; Pathway interactions; Patients; Phase; Plasma; Production; Regulation; Risk; Safety; Signal Transduction; Specificity; Stroke; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Toxic effect; Triglycerides; Vascular Diseases; Work; assay development; blood lipid; drug development; efficacious treatment; genome wide association study; human monoclonal antibodies; hypercholesterolemia; improved; in vitro Assay; in vivo; inhibitor/antagonist; innovation; knock-down; mortality risk; mouse model; nanomolar; new therapeutic target; pre-clinical; prevent; small hairpin RNA; therapeutic target

Inhibiting GPR146 in hypercholesterolemia Abstract Genome-wide association studies have identified the orphan G-protein coupled receptor GPR146 as a potential regulator of plasma cholesterol levels. Recent studies have demonstrated that depletion of GPR146 in mice substantially reduces circulating LDL-cholesterol and triglyceride levels, through activation of ERK signaling and promotion of SREBP2 activity. The lipid-lowering effects of GPR146 depletion by either genetic knock-out or shRNA knock-down protected mice against atherosclerosis in an LDL receptor (LDLR)-independent manner, reducing lesion area by up to 90%. These results strongly suggest that modulation of GPR146 signaling is a viable therapeutic strategy for homozygous familial hypercholesterolemia (HoFH) and potentially other atherosclerotic conditions. The overall goal of this project is to identify and develop a human GPR146 monoclonal antibody (humAb) as an innovative means to treat HoFH. In Phase 1, we will utilize our huFab on phage library to identify a human mAb with high specificity for GPR146. Clones will be rank-ordered by their affinity and specificity using in vitro assays relevant to cholesterol metabolism. Finally, we will evaluate function in vivo using a mouse model. Production of a humAb with a nanomolar Kd, high specificity for GPR146, and ability to prevent atherosclerotic plaque formation will merit submission of a Phase 2 application. Phase 2 work will focus on obtaining the preclinical data necessary for submission of an IND. Pharmacokinetics and toxicity studies, as well as additional animal studies to demonstrate safety and efficacy, will be performed.

抑制高胆固醇血症中的GPR 146 摘要 全基因组关联研究已经将孤儿G蛋白偶联受体GPR 146鉴定为一种新的免疫抑制剂。 血浆胆固醇水平的潜在调节剂。最近的研究表明，GPR 146的消耗在 通过激活ERK信号，小鼠显著降低循环LDL-胆固醇和甘油三酯水平 和促进SREBP 2活性。GPR 146基因敲除的降脂作用 或shRNA敲低保护小鼠以LDL受体（LDLR）非依赖性方式对抗动脉粥样硬化， 将病变面积减少90%。这些结果有力地表明，GPR 146信号转导的调节是一种重要的信号转导途径。 纯合子家族性高胆固醇血症（HoFH）和其他可能的治疗策略 动脉粥样硬化状况。 本项目的总体目标是鉴定和开发人GPR 146单克隆抗体（humAb）， 一种治疗HoFH的创新方法。在第一阶段，我们将利用我们的huFab噬菌体库来鉴定一个人 对GPR 146具有高特异性的mAb。克隆将通过其体外亲和力和特异性进行排序。 与胆固醇代谢相关的测定。最后，我们将使用小鼠模型评估体内功能。 具有纳摩尔Kd、对GPR 146的高特异性和预防动脉粥样硬化能力的humAb的产生 牙菌斑形成将值得提交第2阶段申请。第二阶段的工作将集中在获得 提交IND药代动力学和毒性研究所需的临床前数据，以及其他 将进行动物研究以证明安全性和有效性。