RNA therapeutics
Review surveys the Lp(a)-lowering pipeline from antisense oligonucleotides to CRISPR-Cas9 gene editing (Eur J Clin Invest 2024)
Original title: New insights into the therapeutic options to lower lipoprotein(a)
This review examines Lp(a) as an appealing pharmacological target, given genetic evidence that lower Lp(a) protects against cardiovascular disease independent of other lipid risk factors, despite incompletely understood pathophysiological mechanisms linking Lp(a) to atherosclerosis. Approved lipid-lowering therapies, statins, ezetimibe, and PCSK9 inhibitors, have only a neutral to modest effect on Lp(a), prompting development of dedicated strategies: antisense oligonucleotides and small interfering RNAs targeting apolipoprotein(a), now in advanced clinical development, alongside newer approaches including apo(a) assembly inhibitors and CRISPR-Cas9 gene editing, both in early clinical development. The authors note that if ongoing cardiovascular outcome trials confirm that the more than 80% Lp(a) reductions achieved by pelacarsen, olpasiran, or lepodisiran translate into fewer cardiovascular deaths and major adverse events, Lp(a) lowering will become a new standard target in managing elevated cardiovascular risk.
Original abstract
Background: Elevated levels of lipoprotein(a) [Lp(a)] represent a risk factor for cardiovascular disease including aortic valve stenosis, myocardial infarction and stroke. While the patho-physiological mechanisms linking Lp(a) with atherosclerosis are not fully understood, from genetic studies that lower Lp(a) levels protect from CVD independently of other risk factors including lipids and lipoproteins. Hereby, Lp(a) has been considered an appealing pharmacological target.
Results: However, approved lipid lowering therapies such as statins, ezetimibe or PCSK9 inhibitors have a neutral to modest effect on Lp(a) levels, thus prompting the development of new strategies selectively targeting Lp(a). These include antisense oligonucleotides and small interfering RNAs (siRNAs) directed towards apolipoprotein(a) [Apo(a)], which are in advanced phase of clinical development. More recently, additional approaches including inhibitors of Apo(a) and gene editing approaches via CRISPR-Cas9 technology entered early clinical development.
Conclusion: If the results from the cardiovascular outcome trials, designed to demonstrate whether the reduction of Lp(a) of more than 80% as observed with pelacarsen, olpasiran or lepodisiran translates into the decrease of cardiovascular mortality and major adverse cardiovascular events, will be positive, lowering Lp(a) will become a new additional target in the management of patients with elevated cardiovascular risk.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.