Murphy Beth Ann, Tadin-Strapps Marija, Jensen Kristian, Mogg Robin, Liaw Andy, Herath Kithsiri, Bhat Gowri, McLaren David G, Previs Stephen F, Pinto Shirly
Pharmacology, Merck &Co. Inc., 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA.
Genetics and Pharmacogenomics, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Metabolism. 2017 Jun;71:202-212. doi: 10.1016/j.metabol.2017.02.015. Epub 2017 Mar 6.
SREBP cleavage-activating protein (SCAP) is a cholesterol binding endoplasmic reticulum (ER) membrane protein that is required to activate SREBP transcription factors. SREBPs regulate genes involved in lipid biosynthesis. They also influence lipid clearance by modulating the expression of LDL receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Inhibiting SCAP decreases circulating PCSK9, triglycerides (TG), and LDL-cholesterol (LDL-C), both in vitro and in vivo. Type 2 diabetics with dyslipidemia are at high risk for cardiovascular diseases. These patients present a unique pathophysiological lipid profile characterized by moderately elevated LDL-C, elevated TG and reduced HDL-cholesterol (HDL-C). The spontaneous dysmetabolic rhesus monkey model (DysMet RhM) recapitulates this human dyslipidemia and therefore is an attractive preclinical model to evaluate SCAP inhibition as a therapy for this disease population. The objective to of this study was to assess the effect of SCAP inhibition on the lipid profile of DysMet RhM.
We assessed the effect of inhibiting hepatic SCAP on the lipid profile of DysMet RhM using an siRNA encapsulated lipid nanoparticle (siRNA-LNP).
The SCAP siRNA-LNP significantly reduced LDL-C, PCSK9 and TG in DysMet RhM; LDL-C was reduced by ≥20%, circulating PCSK9 by 30-40% and TG by >25%. These changes by the SCAP siRNA-LNP agree with the predicted effect of SCAP inhibition and reduced SREBP tone on these endpoints.
These data demonstrate that a SCAP siRNA-LNP improved the lipid profile in a clinically relevant preclinical disease model and provide evidence for SCAP inhibition as a therapy for diabetic dyslipidemic patients.
固醇调节元件结合蛋白裂解激活蛋白（SCAP）是一种胆固醇结合内质网（ER）膜蛋白，是激活固醇调节元件结合蛋白（SREBP）转录因子所必需的。SREBP调节参与脂质生物合成的基因。它们还通过调节低密度脂蛋白受体（LDLR）和前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）基因的表达来影响脂质清除。在体外和体内，抑制SCAP均可降低循环中的PCSK9、甘油三酯（TG）和低密度脂蛋白胆固醇（LDL-C）。患有血脂异常的2型糖尿病患者心血管疾病风险很高。这些患者呈现出独特的病理生理脂质谱，其特征为LDL-C中度升高、TG升高和高密度脂蛋白胆固醇（HDL-C）降低。自发性代谢异常恒河猴模型（DysMet RhM）重现了这种人类血脂异常情况，因此是评估SCAP抑制作为该疾病人群治疗方法的有吸引力的临床前模型。本研究的目的是评估SCAP抑制对DysMet RhM脂质谱的影响。
我们使用包裹小干扰RNA的脂质纳米颗粒（siRNA-LNP）评估抑制肝脏SCAP对DysMet RhM脂质谱的影响。
SCAP siRNA-LNP显著降低了DysMet RhM中的LDL-C、PCSK9和TG；LDL-C降低≥20%，循环中的PCSK9降低30 - 40%，TG降低>25%。SCAP siRNA-LNP引起的这些变化与SCAP抑制和SREBP活性降低对这些终点的预期作用一致。
这些数据表明，SCAP siRNA-LNP在临床相关的临床前疾病模型中改善了脂质谱，并为SCAP抑制作为糖尿病血脂异常患者的治疗方法提供了证据。
