siRNA-based therapeutics for lipoprotein (a) lowering: a path toward precision cardiovascular medicine

Abstract

Elevated Lp(a) is recognized as a significant independent risk factor for atherosclerotic cardiovascular diseases, including coronary artery disease, stroke and aortic valve stenosis. Notably, Lp(a) exhibits unique pro-inflammatory and pro-thrombotic properties contributing to its pathogenic role in cardiovascular disease. Although interventions targeting interleukin-6 (IL-6) and proprotein convertase subtilisin/kexin type 9 (PCSK9) have been shown to reduce Lp(a) levels, the extent to which this reduction contributes to their overall cardiovascular benefits remains uncertain. Recent clinical trials have demonstrated that small interfering RNA (siRNA) therapies are effective in lowering Lp(a) levels, prompting ongoing investigations into their potential to improve cardiovascular outcomes. These developments highlight the clinical significance of targeting Lp(a) as a therapeutic strategy. This paper offers a comprehensive review of the pathophysiological role of Lp(a) as an independent cardiovascular risk factor, followed by an in-depth analysis of siRNA-based therapeutics designed to target Lp(a). It examines their mechanisms of action, clinical efficacy and safety profiles, while also addressing potential risks, limitations and challenges associated with Lp(a)-modulating siRNA treatments. Additionally, the review discusses other RNA-based therapeutic approaches for Lp(a) reduction, along with an overview of ongoing clinical trials. Finally, future perspectives are considered to assess the evolving therapeutic landscape and the potential advancements in Lp(a)-targeting strategies for improving cardiovascular outcomes.