RNA therapeutics
Pelacarsen cuts Lp(a) by up to 80%, one of five RNA-targeted drugs reshaping dyslipidaemia treatment, a review (Curr Atheroscler Rep 2021)
Original title: The Role of RNA-Targeted Therapeutics to Reduce ASCVD Risk: What Have We Learned Recently?
This review by Miname, Rocha and Santos surveys RNA-targeted therapies for dyslipidaemia aimed at reducing atherosclerotic cardiovascular disease, covering antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that reduce translation of PCSK9, apolipoprotein B-100, apolipoprotein(a), apolipoprotein C3, and ANGPTL3, mostly using GalNAc-conjugated molecules with high hepatocyte specificity. Inclisiran, an siRNA against PCSK9, achieves robust and well-tolerated LDL-C reductions with injections every 3 to 6 months. Pelacarsen, an ASO against apolipoprotein(a), reduces Lp(a) by up to 80% with good tolerability and is being tested, alongside inclisiran, for ASCVD prevention; AMG 890, an siRNA also targeting apo(a) synthesis, is under investigation. Volanesorsen (targeting apoC3) lowers triglycerides by up to 70%, and vupanorsen (targeting ANGPTL3) lowers triglycerides by 36-53% while also reducing apoC3, non-HDL cholesterol and apoB, though it lowers HDL cholesterol too. The authors describe RNA-targeted therapies as a promising, extensively tested new direction in dyslipidaemia treatment.
Original abstract
Purpose Of Review: To discuss advances on the RNA-targeted therapies to treat dyslipidemia with the aim of reducing atherosclerotic cardiovascular disease (ASCVD).
Recent Findings: Genetic studies have paved the way for therapies that reduce translation of proteins that play causal roles in dyslipidemia and atherosclerosis like proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B-100 (apoB), apolipoprotein(a) [apo(a)], apolipoprotein C3 (apoC3), and angiopoietin-like 3 (ANGPTL3). Either antisense oligonucleotide (ASO) therapies and small interfering RNA (siRNA) molecules inhibit protein synthesis and consequently improve dyslipidemia. Most of these molecules contain N-acetylgalactosamine (GalNAc) moieties that have high specificity for hepatocytes and therefore reduce concentration in other tissues. Inclisiran, an siRNA for PCSK9, has shown robust LDL-C reductions, with good tolerability, in severe forms of hypercholesterolemia as well as in high cardiovascular disease patients with injections every 3 to 6 months. Pelacarsen is an ASO against apolipoprotein(a) that reduces Lp(a) up to 80% with good tolerability. Either inclisiran or pelacarsen is being tested to show it can prevent ASCVD. AMG 890, an siRNA compound aimed at reducing apo(a) synthesis, is also under investigation. Volanesorsen is an ASO against apoC3 that reduces triglyceride levels up to 70% and is being tested in severe hypertriglyceridemic patients. Vupanorsen is an ASO against ANGPTL3 that reduced triglyceride levels 36-53% among moderate hypertriglyceridemic individuals. Interestingly, it also reduces ApoC3 and non-HDL cholesterol and apoB; however, it lowers HDL cholesterol. RNA-targeted therapies are being extensively tested for dyslipidemia treatment with promising results.
PCSK9 inhibitionpelacarsenRNA therapeutics
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.