Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy.
Trends Pharmacol Sci. 2013 Apr;34(4):198-205. doi: 10.1016/j.tips.2013.01.010. Epub 2013 Feb 26.
The key role of dyslipidaemias in determining cardiovascular risk has been well established, and statins often provide effective therapeutic management. However, many patients do not achieve recommended lipid levels despite maximal therapy, and some cannot tolerate high-dose statin therapy. Recently, genetic insights into mechanisms underlying regulation of lipoprotein metabolism have expanded the potential targets of drug therapy and led to the development of novel agents, including development of gene silencing approaches. These therapeutic options include the modulation of synthesis in the liver, maturation in the circulation, and catabolism of lipoproteins. In this review, we discuss the pharmacological consequences of silencing apolipoprotein B, apolipoprotein (a), microRNA 33, proprotein convertase subtilisin/kexin type 9, and apolipoprotein C-III. New potential targets such as other microRNAs, diacylglycerol acyl transferase-1, and angiopoietin-like protein 3 are also presented. The pharmacological consequences of gene silencing and the advancement of these therapeutic approaches in clinical development will be examined.
脂质代谢紊乱在确定心血管风险方面起着关键作用，而他汀类药物通常可提供有效的治疗管理。然而，尽管采用了最大剂量的治疗，许多患者仍未达到推荐的血脂水平，有些患者不能耐受高剂量他汀类药物治疗。最近，对脂蛋白代谢调节机制的遗传研究为药物治疗的潜在靶点提供了扩展，并导致了新型药物的开发，包括基因沉默方法的开发。这些治疗选择包括调节肝脏中的合成、循环中的成熟和脂蛋白的代谢。在这篇综述中，我们讨论了沉默载脂蛋白 B、载脂蛋白(a)、微小 RNA33、脯肽酶枯草溶菌素/凝血酶 9 和载脂蛋白 C-III 的药理学后果。还介绍了其他一些新的潜在靶点，如其他微小 RNA、二酰基甘油酰基转移酶-1 和血管生成素样蛋白 3。本文还将研究基因沉默的药理学后果以及这些治疗方法在临床开发中的进展。
