Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Where Do We Stand?

Abstract

Lipoprotein(a) [Lp(a)] consists of a low-density lipoprotein-like molecule and an apolipoprotein(a) [apo(a)] particle. Lp(a) has been suggested to be an independent risk factor of atherosclerotic cardiovascular disease (ASCVD). Lp(a) plasma levels are considered to be 70-90% genetically determined through the codominant expression of the LPA gene. Therefore, Lp(a) levels are almost stable during an individual's lifetime. This lifelong stability, together with the difficulties in measuring Lp(a) levels in a standardized manner, may account for the scarcity of available drugs targeting Lp(a). In this review, we synopsize the latest data regarding the structure, metabolism, and factors affecting circulating levels of Lp(a), as well as the laboratory determination measurement of Lp(a), its role in the pathogenesis of ASCVD and thrombosis, and the potential use of various therapeutic agents targeting Lp(a). In particular, we discuss novel agents, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that are currently being developed and target Lp(a). The promising role of muvalaplin, an oral inhibitor of Lp(a) formation, is then further analyzed.

Keywords: antisense oligonucleotides; atherosclerosis; cardiovascular disease; chronic inflammation; lepodisiran; lipoprotein(a); muvalaplin; small interfering RNAs.

Figure 1

Structure of lipoprotein(a). Lipoprotein(a) is a variant of LDL, distinguished by the binding of ApoB100 to apolipoprotein(a) via a disulfide thioester bond. Abbreviations: ApoB100, Apolipoprotein B100; KIV, kringle IV. LDL, low-density lipoprotein. Parts of the figure are from the free medical site http://smart.servier.com/ (accessed on 10 March 2024) by Servier licensed under a Creative Commons BY 4.0 License https://creativecommons.org/licenses/by/4.0/ (accessed on 10 March 2024).

Figure 2

Genetic and non-genetic factors affecting lipoprotein(a) levels. Abbreviations: Apo(a), Apolipoprotein(a); KIV, kringle IV; SNPs, single nucleotide polymorphisms. Parts of the figure are from the free medical site http://smart.servier.com/ by Servier licensed under a Creative Commons BY 4.0 License https://creativecommons.org/licenses/by/4.0/).

Figure 3

The role of lipoprotein(a) in human disease. Elements of the figure are from the free medical site http://smart.servier.com/ by Servier licensed under a Creative Commons BY 4.0 License https://creativecommons.org/licenses/by/4.0/.

Figure 4

Schematic presentation of the emerging molecular Lp(a)-targeting therapies: (A). Pelacarsen is the only ASO that specifically targets the formation of Lp(a). Upon conjugation with GalNAc, the complex undergoes endocytosis into hepatocytes via ASGPR. Subsequently, the translation of mRNA encoding for LPA is inhibited, leading to reduced formation of apo(a). (B). Once inside the hepatocytes, siRNAs are incorporated into the RISC. Thereafter, they bind to the mRNA encoding for apo(a). This binding triggers the degradation of the apo(a) mRNA, ultimately leading to the inhibition of LPA gene expression. (C). Muvalaplin binds to the apo(a) KIV7 and KIV8 domains, causing disruption of the noncovalent interaction between apo(a) and ApoB100. As a result, inhibition of the Lp(a) formation is observed (D). AAV facilitates the transfer of CRISPR in the liver, where CRISPR disrupts the LPA gene, resulting in the removal of Lp(a) particles from the plasma [236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254]. Abbreviations: AAV: adeno-associated virus; apo(a): apolipoprotein(a); ApoB100: apolipoproteinB100; ASGPR, Asialoglycoprotein receptor; ASO: antisense oligonucleotide; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeat; GalNAc: N-Acetylgalactosamine; KIV: kringle IV; Lp(a): lipoprotein(a); mRNA, messenger RNA; RISC: RNA-induced silencing complex; RNAase: ribonuclease; siRNA: small-interfering RNA. Created with BioRender.com.