Inhibiting GPR146 in hypercholesterolemia

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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.