RNA therapeutics
A pharmacology review surveys the antisense, siRNA and small-molecule agents advancing Lp(a) therapy beyond LDL pathways (J Pharmacol Exp Ther 2025)
Original title: Emerging therapies targeting lipoprotein(a): Pharmacologic advances and future directions
This review addresses why residual atherosclerotic cardiovascular disease risk persists despite advances in LDL-targeted therapy, framing lipoprotein(a), genetically determined, proatherogenic, proinflammatory and prothrombotic, as a biomarker affecting roughly 20% to 30% of the global population that traditional antilipemic agents barely touch. It surveys the emerging pharmacologic classes now in development to lower Lp(a) directly, including antisense oligonucleotides, small interfering RNA agents and small molecules, alongside further-horizon approaches such as gene editing. The authors argue that early clinical trial efficacy signals across these modalities point to a new era of ASCVD prevention through non-LDL pathways, and that clinicians will need a working understanding of these agents ahead of anticipated market approvals. A pharmacology-oriented survey rather than new trial data.
Original abstract
Despite advances in therapies that target low-density lipoprotein (LDL), atherosclerotic cardiovascular disease (ASCVD) remains a major cause of morbidity and mortality. This has led to the investigation of other biomarkers, including lipoprotein(a) [Lp(a)]. Lp(a) is a variant of LDL that is genetically determined, has proatherogenic, proinflammatory, and prothrombotic effects, and has a linear correlation with ASCVD risk. Approximately 20%-30% of the global population has elevated serum Lp(a). Recommendations for increased Lp(a) testing has heightened the need for effective medications to target this biomarker. Although traditional antilipemic agents have demonstrated negligible effects on Lp(a), multiple targeted therapies are emerging, including antisense oligonucleotides, small interfering RNA agents, and small molecules. The efficacy of these novel agents observed in early clinical trials and the development of alternate treatment modalities, including gene editing and RNA-based innovations, signal a promising new era of ASCVD prevention via non-LDL pathways. SIGNIFICANCE STATEMENT: Lipoprotein(a) is a genetically determined biomarker that significantly impacts atherosclerotic risk. The development of novel therapies that lower lipoprotein(a) warrants a broad understanding to increase comfortability and optimize utilization upon market approval.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.