title: Dose-dependent effects of siRNA-mediated inhibition of SCAP on PCSK9, LDLR, and plasma lipids in mouse and rhesus monkey.
abstract: SREBP cleavage-activating protein (SCAP) is a key protein in the regulation of lipid metabolism and a potential target for treatment of dyslipidemia. SCAP is required for activation of the transcription factors SREBP-1 and -2. SREBPs regulate the expression of genes involved in fatty acid and cholesterol biosynthesis, and LDL-C clearance through the regulation of LDL receptor (LDLR) and PCSK9 expression. To further test the potential of SCAP as a novel target for treatment of dyslipidemia, we used siRNAs to inhibit hepatic SCAP expression and assess the effect on PCSK9, LDLR, and lipids in mice and rhesus monkeys. In mice, robust liver Scap mRNA knockdown (KD) was achieved, accompanied by dose-dependent reduction in SREBP-regulated gene expression, de novo lipogenesis, and plasma PCSK9 and lipids. In rhesus monkeys, over 90% SCAP mRNA KD was achieved resulting in approximately 75, 50, and 50% reduction of plasma PCSK9, TG, and LDL-C, respectively. Inhibition of SCAP function was demonstrated by reduced expression of SREBP-regulated genes and de novo lipogenesis. In conclusion, siRNA-mediated inhibition of SCAP resulted in a significant reduction in circulating PCSK9 and LDL-C in rodent and primate models supporting SCAP as a novel target for the treatment of dyslipidemia.
authors.affiliation: Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. Electronic address: kristian_jensen@merck.com.
authors.forename: Kristian K
authors.initials: KK
authors.lastname: Jensen
authors.affiliation: Genetics and Pharmacogenomics, Merck & Co. Inc., Boston, MA.
authors.forename: Marija
authors.initials: M
authors.lastname: Tadin-Strapps
authors.affiliation: Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ.
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ.
authors.forename: James
authors.initials: J
authors.lastname: Hubert
authors.affiliation: Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Kan
authors.affiliation: Sirna Therapeutics Merck & Co. Inc., San Francisco, CA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Pharmacology, Merck & Co. Inc., Kenilworth, NJ.
authors.forename: David G
authors.initials: DG
authors.lastname: McLaren
authors.affiliation: Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Previs
authors.affiliation: Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ.
authors.forename: Kithsiri B
authors.initials: KB
authors.lastname: Herath
authors.affiliation: Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ.
authors.forename: Ablatt
authors.initials: A
authors.lastname: Mahsut
authors.affiliation: Biostatistics, Merck & Co. Inc., Rahway, NJ.
authors.forename: Andy
authors.initials: A
authors.lastname: Liaw
authors.affiliation: Biostatistics, Merck & Co. Inc., Rahway, NJ.
authors.forename: Shubing
authors.initials: S
authors.lastname: Wang
authors.affiliation: Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Stout
authors.affiliation: Pharmacology, Merck & Co. Inc., Kenilworth, NJ.
authors.forename: CarolAnn
authors.initials: C
authors.lastname: Keohan
authors.affiliation: Pharmacology, Merck & Co. Inc., Kenilworth, NJ.
authors.forename: Gail
authors.initials: G
authors.lastname: Forrest
authors.affiliation: Sirna Therapeutics Merck & Co. Inc., San Francisco, CA.
authors.forename: David
authors.initials: D
authors.lastname: Coelho
authors.affiliation: Sirna Therapeutics Merck & Co. Inc., San Francisco, CA.
authors.forename: Satya
authors.initials: S
authors.lastname: Yendluri
authors.affiliation: RNA Therapeutics, Merck & Co. Inc., West Point, PA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Williams
authors.affiliation: RNA Therapeutics, Merck & Co. Inc., West Point, PA.
authors.forename: Martin
authors.initials: M
authors.lastname: Koser
authors.affiliation: Business Development and Licensing, Merck & Co. Inc., San Francisco, CA.
authors.forename: Steven
authors.initials: S
authors.lastname: Bartz
authors.affiliation: Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ.
authors.forename: Karen O
authors.initials: KO
authors.lastname: Akinsanya
authors.affiliation: Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ.
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
mesh_terms: D000818:Animals; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008055:Lipids / Q000097:blood*; D050155:Lipogenesis; D008099:Liver / Q000201:enzymology; D008253:Macaca mulatta; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D000071449:Proprotein Convertase 9 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000960:Hypolipidemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011973:Receptors, LDL; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins; D019821:Simvastatin; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9
keywords: SREBP cleavage-activating protein; animal models; cardiometabolic disease; cholesterol; drug therapy; dyslipidemia; lipid and lipoprotein metabolism; lipids/liver; low density lipoprotein; metabolic disease; proprotein convertase subtilisin kexin type 9; small interfering ribonucleic acid