Updates in Small Interfering RNA for the Treatment of Dyslipidemias

Abstract

Purpose of review: Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders.

Recent findings: The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.

Keywords: ARO-ANG3; ARO-APOC3; Inclisiran; Lipid-lowering therapy; Olpasiran.

Fig. 1

Small interfering RNA (siRNA) structure and mechanism. a siRNA structure; b siRNA conjugated with N-acetylgalactosamine (GalNac); c once in the cytoplasm the two strands of siRNA are separated with the guide loaded into the RISC and the passenger removed and degraded. When the complementary target mRNA has hybridized with part of the guide strand, an endonucleolytic cleavage of the mRNA is driven by a component of RISC, the Argonaute 2 (ago 2) protein. (Modified with permission from: [Panel a] John Wiley and Sons ©2022 [24]; [Panel b] American Chemical Society ©2014 [25]; and [Panel c] Elsevier ©2019 [26])

Fig. 2

siRNA to reduce atherogenic lipoproteins. Inclisiran to lower LDL-C; olpasiran to lower lipoprotein(a); ARO-APOC3 and ARO-ANG3 to lower triglyceride-rich lipoproteins. ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); TG, triglycerides; TRL, triglyceride-rich lipoprotein VLDL-C, very low-density lipoprotein cholesterol. (Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License https://creativecommons.org/licenses/by/3.0/)