Dose-dependent effects of siRNA-mediated inhibition of SCAP on PCSK9, LDLR, and plasma lipids in mouse and rhesus monkey[S]

Journal of Lipid Research

Marija Tadin-Strapps¹  Yong Ma²  Shirly Pinto³  David Coelho³  Stephen F. Previs³  Ablatt Mahsut³  Sheng-ping Wang³  Stephanie Williams³  Shubing Wang³  Steven Bartz³  CarolAnn Keohan⁴  James Hubert⁵  Andy Liaw⁶  Kithsiri B. Herath⁶  David G. McLaren⁶  Martin Koser⁶  Karen O. Akinsanya⁶  Satya Yendluri⁶  Yanqing Kan⁷  Gail Forrest⁸  Steven J. Stout⁹  Kristian K. Jensen^1,10 

[1] Cardiometabolic Disease Merck &Co. Inc., Boston, MA;Co. Inc., Kenilworth, NJ;Co. Inc., San Francisco, CA;To whom correspondence should be addressed;;Cardiometabolic Disease Merck &;Genetics and Pharmacogenomics, Merck &;Pharmacology, Merck &;Sirna Therapeutics Merck &To whom correspondence should be addressed;

关键词: lipid and lipoprotein metabolism;    metabolic disease;    lipids/liver;    animal models;    low density lipoprotein;    drug therapy;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown