Targeting Lipoprotein(a): Can RNA Therapeutics Provide the Next Step in the Prevention of Cardiovascular Disease?

Abstract

Numerous genetic and epidemiologic studies have demonstrated an association between elevated levels of lipoprotein(a) (Lp[a]) and cardiovascular disease. As a result, lowering Lp(a) levels is widely recognized as a promising strategy for reducing the risk of new-onset coronary heart disease, stroke, and heart failure. Lp(a) consists of a low-density lipoprotein-like particle with covalently linked apolipoprotein A (apo[a]) and apolipoprotein B-100, which explains its pro-thrombotic, pro-inflammatory, and pro-atherogenic properties. Lp(a) serum concentrations are genetically determined by the apo(a) isoform, with shorter isoforms having a higher rate of particle synthesis. To date, there are no approved pharmacological therapies that effectively reduce Lp(a) levels. Promising treatment approaches targeting apo(a) expression include RNA-based drugs such as pelacarsen, olpasiran, SLN360, and lepodisiran, which are currently in clinical trials. In this comprehensive review, we provide a detailed overview of RNA-based therapeutic approaches and discuss the recent advances and challenges of RNA therapeutics specifically designed to reduce Lp(a) levels and thus the risk of cardiovascular disease.

Keywords: Cardiovascular disease; Elevated Lp(a) levels; Lepodisiran (LY3819469); Lipoprotein(a); Olpasiran; Pelacarsen; RNA therapeutics; SLN360; Therapy.

Fig. 1

Overview of gene-silencing mechanisms of RNA-based therapeutics. a ASOs bind to target mRNAs, resulting in RNase H1 cleavage or steric blockade of translation initiation and protein expression. Steric-blocking ASOs can also be used to express a different protein isoform by initiating alternative splicing. b The guide strand of the siRNA enters the RISC, and the activated complex cleaves the target mRNA. c Therapeutics based on mRNA are expressed by the cell's own synthesis machinery and encode a target protein. d MiRNA drugs act by binding and cleaving the target mRNA, thereby inhibiting protein translation, or by competing with endogenous miRNAs, preventing mRNA cleavage by blocking the RISC and allowing protein expression. ASOs antisense oligonucleotides, siRNA small interfering RNA, mRNA messenger RNA, miRNA microRNA, RISC RNA-induced silencing complex. Created with BioRender.com

Fig. 2

Structure of LDL-C and Lp(a) particle. a LDL-C consists of a lipid particle, associated with apoB-100. b Lp(a) consists of an LDL-like particle with apo(a). The length of the apo(a) isoform depends on the number of kringle IV (KIV) repeats. The shorter the apo(a) isoform, the higher the particle number. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein(a), Apo(a) apolipoprotein(a), ApoB-100 apolipoprotein B-100. Created with BioRender.com

Fig. 3

Pathological mechanism of Lp(a). Lp(a) has pro-thrombotic, pro-atherogenic, and pro-inflammatory properties. Lp(a) interferes with plasminogen activation and fibrin degradation by promoting prothrombin activation. OxPL on the particle surface makes Lp(a) pro-inflammatory and induces monocyte activation and transmigration. Lp(a) is associated with atherosclerosis by promoting foam cell formation, necrotic core formation, endothelial cell binding, and smooth muscle cell proliferation. As a result of plaque formation and rupture, individuals with elevated serum concentrations may experience myocardial infarction and ischemic stroke. Turbulent blood flow and calcification can lead to atherosclerotic stenosis and aortic valve stenosis [163, 206, 207]; SMC smooth muscle cell, EC endothelial cell, Lp(a) lipoprotein(a), Apo(a) apolipoprotein(a), ApoB-100 apolipoprotein B-100, OxPL oxidized phospholipids. Created with BioRender.com