title: siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids.
abstract: 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.
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA. Electronic address: marija_tadin-strapps@merck.com.
authors.forename: Marija
authors.initials: M
authors.lastname: Tadin-Strapps
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Peterson
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cumiskey
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Rosa
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Vivienne Halili
authors.initials: VH
authors.lastname: Mendoza
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Jose
authors.initials: J
authors.lastname: Castro-Perez
authors.affiliation: Guided Solutions, Merck & Co., Inc., Rahway, NJ.
authors.forename: Oscar
authors.initials: O
authors.lastname: Puig
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Liwen
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA.
authors.forename: Walter R
authors.initials: WR
authors.lastname: Strapps
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA.
authors.forename: Satyasri
authors.initials: S
authors.lastname: Yendluri
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA.
authors.forename: Lori
authors.initials: L
authors.lastname: Andrews
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Pickering
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA.
authors.forename: Julie
authors.initials: J
authors.lastname: Rice
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA.
authors.forename: Lily
authors.initials: L
authors.lastname: Luo
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA.
authors.forename: Samnang
authors.initials: S
authors.lastname: Tep
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Ason
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Elizabeth Polizzi
authors.initials: EP
authors.lastname: Somers
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Sachs
authors.affiliation: Sirna Therapeutics, Inc., San Francisco, CA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Bartz
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Jenny
authors.initials: J
authors.lastname: Tian
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Jayne
authors.initials: J
authors.lastname: Chin
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Hubbard
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Kenny K
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
authors.forename: Lyndon J
authors.initials: LJ
authors.lastname: Mitnaul
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics*; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood*; D004195:Disease Models, Animal; D018703:Founder Effect; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D057898:Hemizygote; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008081:Liposomes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D008081:Liposomes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D014280:Triglycerides