Abstract 13054: The Novel Galnac-Conjugated Rnai Trigger Downregulates Apoc3 and Triglyceride Levels in Humanized Liver Mouse Model

Abstract

Background: Hypertriglyceridemia is a critical risk factor for coronary artery disease. Apolipoprotein C-III (APOC3), produced by liver hepatocytes, regulates triglyceride (TG) levels. We studied effect of novel GalNAc-conjugated APOC3 targeting RNAi trigger (STP125G) on APOC3 and TG levels in humanized liver mouse model. Methods: In dose response study, female uPA-SCID mice (n=4 mice/group), group 1 received PBS control, group 2 received 10mg/kg and group 3 received 30mg/kg STP125G, subcutaneously on day 0. Liver biopsies, plasma and serum samples were collected at week 2. In duration response study, male uPA-SCID mice (n=4 mice/group/timepoint), group 1 received PBS control and group 2 received 10mg/kg STP125G, subcutaneously on day 0. Liver biopsies, plasma and serum samples were collected for each group at weeks 2, 4, 8 and 12. Human APOC3 mRNA (qPCR) and protein (ELISA) levels were measured in liver biopsies and plasma samples, respectively. TGs and total cholesterol (TC) levels were measured in serum samples. Results: In dose response study, animals reported significant suppression of mRNA and reduction of plasma protein levels in 10mg/kg (88% and 91%, respectively) and 30mg/kg (92% and 98%, respectively) dose groups as compared to control group ( p <0.001). Animals also reported significant reductions in TGs and TC levels at 10mg/kg (25% and 33%, respectively) and 30mg/kg (43% and 44%, respectively) dose groups as compared to control group ( p <0.05). In duration response study, treated animals reported significant suppression of mRNA levels at week 2 (83%), week 4 (85%) and week 8 (48%) as compared to control group ( p <0.0001). Treated animals reported significant reduction in plasma protein levels at week 2 (82%; p <0.0001), week 4 (89%; p <0.0001) and week 8 (70%; p =0.0005) as compared to control group. At week 4, treated animals reported significant reduction in TGs (53%; p=0.0079) and TC (36%; p=0.0072). Conclusions: The studies demonstrated that a single administration of STP125G, in a humanized liver mouse model, results in significant suppression of human APOC3 mRNA and plasma protein levels that lasts for up to 8 weeks. It also suggests treatment with STP125G results in lowering of triglycerides and total cholesterol in the treated animals.