Inhibiting GPR146 in hypercholesterolemia

抑制GPR146在高胆固醇血症中的作用 摘要 全基因组关联研究发现，孤儿G蛋白偶联受体GPR146是一种 血浆胆固醇水平的潜在调节者。最近的研究表明，在中国，GPR146的枯竭 小鼠通过激活ERK信号显著降低循环中的低密度脂蛋白和甘油三酯水平 和促进SREBP2活动。两种基因敲除导致的GPR146缺失的降脂作用 或shRNA以不依赖于低密度脂蛋白受体(LDLR)的方式保护小鼠免受动脉粥样硬化的影响， 减少高达90%的病变面积。这些结果有力地表明，GPR146信号的调制是一种 纯合子家族性高胆固醇血症(HoFH)和其他潜在疾病的可行治疗策略 动脉粥样硬化的情况。 本项目的总体目标是鉴定和开发一种人GPR146单抗(HumAb)作为 一种治疗HoFH的创新方法。在第一阶段，我们将使用噬菌体库上的huFab来识别人类 对GPR146具有高度特异性的单抗。克隆将根据它们的亲和力和特异性在体外进行排序 与胆固醇代谢相关的化验。最后，我们将使用小鼠模型来评估体内的功能。 抗GPR146抗体的制备及其抗动脉粥样硬化作用的研究 斑块形成将值得提交第二阶段申请。第二阶段的工作将集中在获得 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 将进行动物实验，以证明安全性和有效性。

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.