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.

在高胆固醇血症中抑制GPR146 抽象的 全基因组关联研究已将孤儿G蛋白偶联受体GPR146鉴定为A 血浆胆固醇水平的潜在调节剂。最近的研究表明，GPR146在 小鼠通过激活ERK信号传导，实质上降低了循环的LDL-胆固醇和甘油三酸酯水平 和促进SREBP2活性。 GPR146的降低降低效应，这两种遗传敲除 或shRNA敲低的小鼠免受LDL受体（LDLR）非依赖性的动脉粥样硬化的影响， 将病变面积减少多达90％。这些结果强烈表明GPR146信号的调制是一个 纯合家族性高胆固醇血症（HOFH）的可行治疗策略以及其他可能 动脉粥样硬化条件。 该项目的总体目标是识别和开发人类GPR146单克隆抗体（Humab） 一种创新的方法来治疗霍夫。在第1阶段，我们将在噬菌体库上利用我们的HUFAB来识别人类 对GPR146具有高特异性的mAb。克隆将使用体外的亲和力和特异性来订购克隆 与胆固醇代谢相关的测定。最后，我们将使用鼠标模型在体内评估功能。 产生具有纳摩尔KD的Humab，GPR146的高特异性以及预防动脉粥样硬化的能力 牙菌斑的形成值应提交2阶段申请。第2阶段的工作将集中于获得 提交IND所需的临床前数据。药代动力学和毒性研究以及其他 将进行动物研究以证明安全性和有效性。