siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids

Increased serum apolipoprotein (apo)B and associated LDL levels are well-correlated with an increased risk of coronary disease. ApoE(-/-) and low density lipoprotein receptor (LDLr)(-/-) mice have been extensively used for studies of coronary atherosclerosis. These animals show atherosclerotic lesions similar to those in humans, but their serum lipids are low in apoB-containing LDL particles. We describe the development of a new mouse model with a human-like lipid profile. Ldlr(+/-) CETP+/- hemizygous mice carry a single copy of the human CETP transgene and a single copy of a LDL receptor mutation. To evaluate the apoB pathways in this mouse model, we used novel short-interfering RNAs (siRNA) formulated in lipid nanoparticles (LNP). ApoB siRNAs induced up to 95% reduction of liver ApoB mRNA and serum apoB protein, and a significant lowering of serum LDL in Ldlr(+/-) CETP+/- mice. ApoB targeting is specific and dose-dependent, and it shows lipid-lowering effects for over three weeks. Although specific triglycerides (TG) were affected by ApoB mRNA knockdown (KD) and the total plasma lipid levels were decreased by 70%, the overall lipid distribution did not change. Results presented here demonstrate a new mouse model for investigating additional targets within the ApoB pathways using the siRNA modality.-Tadin-Strapps, M., L. B. Peterson, A-M. Cumiskey, R. L. Rosa, V. H. Mendoza, J. Castro-Perez, O. Puig, L. Zhang, W. R. Strapps, S. Yendluri, L. Andrews, V. Pickering, J. Rice, L. Luo, Z. Chen, S. Tep, B. Ason, E. P. Somers, A. B. Sachs, S. R. Bartz, J. Tian, J. Chin, B. K. Hubbard, K. K. Wong, and L. J. Mitnaul. siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids. J. Lipid Res. 2011. 52: 1084-1097.