PMID- 21398511
OWN - NLM
STAT- MEDLINE
DCOM- 20110919
LR  - 20211020
IS  - 1539-7262 (Electronic)
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 52
IP  - 6
DP  - 2011 Jun
TI  - siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model 
      with human-like serum lipids.
PG  - 1084-1097
LID - S0022-2275(20)31327-4 [pii]
LID - 10.1194/jlr.M012872 [doi]
AB  - 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.
FAU - Tadin-Strapps, Marija
AU  - Tadin-Strapps M
AD  - Sirna Therapeutics, Inc., San Francisco, CA. Electronic address: 
      marija_tadin-strapps@merck.com.
FAU - Peterson, Laurence B
AU  - Peterson LB
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Cumiskey, Anne-Marie
AU  - Cumiskey AM
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Rosa, Raymond L
AU  - Rosa RL
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Mendoza, Vivienne Halili
AU  - Mendoza VH
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Castro-Perez, Jose
AU  - Castro-Perez J
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Puig, Oscar
AU  - Puig O
AD  - Guided Solutions, Merck & Co., Inc., Rahway, NJ.
FAU - Zhang, Liwen
AU  - Zhang L
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Strapps, Walter R
AU  - Strapps WR
AD  - Sirna Therapeutics, Inc., San Francisco, CA.
FAU - Yendluri, Satyasri
AU  - Yendluri S
AD  - Sirna Therapeutics, Inc., San Francisco, CA.
FAU - Andrews, Lori
AU  - Andrews L
AD  - Sirna Therapeutics, Inc., San Francisco, CA.
FAU - Pickering, Victoria
AU  - Pickering V
AD  - Sirna Therapeutics, Inc., San Francisco, CA.
FAU - Rice, Julie
AU  - Rice J
AD  - Sirna Therapeutics, Inc., San Francisco, CA.
FAU - Luo, Lily
AU  - Luo L
AD  - Sirna Therapeutics, Inc., San Francisco, CA.
FAU - Chen, Zhu
AU  - Chen Z
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Tep, Samnang
AU  - Tep S
AD  - Sirna Therapeutics, Inc., San Francisco, CA.
FAU - Ason, Brandon
AU  - Ason B
AD  - Sirna Therapeutics, Inc., San Francisco, CA.
FAU - Somers, Elizabeth Polizzi
AU  - Somers EP
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Sachs, Alan B
AU  - Sachs AB
AD  - Sirna Therapeutics, Inc., San Francisco, CA.
FAU - Bartz, Steven R
AU  - Bartz SR
AD  - Sirna Therapeutics, Inc., San Francisco, CA.
FAU - Tian, Jenny
AU  - Tian J
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Chin, Jayne
AU  - Chin J
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Hubbard, Brian K
AU  - Hubbard BK
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Wong, Kenny K
AU  - Wong KK
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
FAU - Mitnaul, Lyndon J
AU  - Mitnaul LJ
AD  - Division of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ.
LA  - eng
PT  - Journal Article
DEP - 20110311
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (Apolipoproteins B)
RN  - 0 (Apolipoproteins E)
RN  - 0 (CETP protein, human)
RN  - 0 (Cholesterol Ester Transfer Proteins)
RN  - 0 (Cholesterol, LDL)
RN  - 0 (Liposomes)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, LDL)
RN  - 0 (Triglycerides)
SB  - IM
MH  - Animals
MH  - Apolipoproteins B/blood/*genetics
MH  - Apolipoproteins E/blood/genetics
MH  - Atherosclerosis/*genetics/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cholesterol Ester Transfer Proteins/*genetics/metabolism
MH  - Cholesterol, LDL/*blood
MH  - *Disease Models, Animal
MH  - Founder Effect
MH  - Gene Expression Profiling
MH  - Gene Knockdown Techniques
MH  - Hemizygote
MH  - Humans
MH  - Lipid Metabolism/genetics
MH  - Liposomes/metabolism
MH  - Liver/drug effects/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Nanoparticles/administration & dosage
MH  - RNA, Messenger/analysis/biosynthesis
MH  - RNA, Small Interfering/metabolism/pharmacology
MH  - Receptors, LDL/*genetics/metabolism
MH  - Triglycerides/blood
PMC - PMC3090230
EDAT- 2011/03/15 06:00
MHDA- 2011/09/20 06:00
PMCR- 2012/06/01
CRDT- 2011/03/15 06:00
PHST- 2011/03/15 06:00 [entrez]
PHST- 2011/03/15 06:00 [pubmed]
PHST- 2011/09/20 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - S0022-2275(20)31327-4 [pii]
AID - m012872 [pii]
AID - 10.1194/jlr.M012872 [doi]
PST - ppublish
SO  - J Lipid Res. 2011 Jun;52(6):1084-1097. doi: 10.1194/jlr.M012872. Epub 2011 Mar 
      11.