RNA Silencing in the Management of Dyslipidemias

Abstract

Purpose of review: Remarkable reductions in cardiovascular morbidity and mortality have been achieved in recent decades through the widespread use of 'small-molecule' hypolipidaemic drugs such as statins and ezetimibe. An alternative approach is to perturb the production of proteins through ribonucleic acid (RNA) silencing, leading to long-lasting knock-down of specific biological molecules. This review describes the scientific basis of RNA silencing, and critically evaluates the evidence relating to inclisiran, a small interfering RNA against proprotein convertase subtilisin kexin 9 (PCSK9).

Recent findings: Pooled analysis of three recent ORION trials has demonstrated that twice-yearly administration of inclisiran reduces LDL-C by 50% in a range of patient groups, with only mild adverse effects. Inclisiran provides safe, effective and long-lasting reductions in PCSK9 and LDL-C. The results of the phase-3 ORION-4 outcomes study are eagerly awaited. Further promising RNA silencing technologies have the potential to improve the management of dyslipidaemia.

Keywords: Atherosclerosis; Dyslipidaemia; Inclisiran; LDL cholesterol; siRNA.

Fig. 1

Mechanisms of action of lipid-lowering drugs in hepatocytes. (1) LDL is cleared from plasma through binding with LDL receptor (LDL-R) and internalisation; LDL-R binds to PCSK9 and is internalised and degraded. (2) Monoclonal antibody PCSK9 inhibitors (alirocumab and evolocumab) bind to PCSK9 and prevent its interaction with LDL-R, thereby increasing LDL-R on the cell surface. (3) Inclisiran produces long-lasting reduction in PCSK9 by silencing mRNA for PCSK9, thereby increasing LDL-R on the cell surface. (4) Statins reduce cholesterol production by inhibition of HMG-CoA reductase, the rate-limiting step in the mevalonate pathway; this leads to an upregulation of LDL-R on the cell surface. Abbreviations: CoA, coenzyme A; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; LDL, low-density lipoprotein; MoAbs, monoclonal antibodies; mRNA, messenger ribonucleic acid; PCSK9 proprotein convertase subtilisin kexin 9; RISC, RNA-induced silencing complex (figure was created with biorender.com)