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

• Published in: Cardiology and Therapy Vol. 13; no. 1; pp. 39 - 67
• Main Authors: Thau, Henriette, Neuber, Sebastian, Emmert, Maximilian Y., Nazari-Shafti, Timo Z.
• Format: Journal Article
• Language: English
• Published: Cheshire Springer Healthcare 01.03.2024; Springer; Adis, Springer Healthcare
• Subjects: Apolipoproteins; Cardiology; Cardiovascular disease; Cardiovascular diseases; Coronary heart disease; Elevated Lp(a) levels; Fomivirsen; Genetic aspects; Health aspects; Heart failure; Internal Medicine; Lepodisiran (LY3819469); Lipoprotein A; Low density lipoproteins; Measurement; Medicine; Medicine & Public Health; Mipomersen; Olpasiran; Pelacarsen; Prevention; Review; Risk factors; Germany; Lepodisiran (LY3819469); Therapy; Lipoprotein(a); Elevated Lp(a) levels; Olpasiran; Pelacarsen; Cardiovascular disease; RNA therapeutics; SLN360
• ISSN: 2193-8261; 2193-6544
• DOI: 10.1007/s40119-024-00353-w

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.