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

ABSTRACT: 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.

SUBMITTER: Thau H

PROVIDER: S-EPMC10899152 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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

Thau Henriette H Neuber Sebastian S Emmert Maximilian Y MY Nazari-Shafti Timo Z TZ

Cardiology and therapy 20240221 1

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-inflamma ...[more]

PMID: 38381282

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Project description:Purpose of reviewThe primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on optimizing cardiovascular health and appropriate pharmacotherapy, a mainstay of which is low-density lipoprotein-cholesterol (LDL-C) lowering. Typically, statin therapy remains the first line approach. Advances in technology and understanding of lipid metabolism have facilitated the development of several novel therapeutic targets and medications within the last decade. This review focuses on medications recently approved by the U.S. Food and Drug Administration (FDA) for the reduction of LDL-C and ASCVD risk, as well as new therapies in the pipeline.Recent findingsNovel lipid therapies aim to lower risk of ASCVD by targeting reduction of atherogenic compounds, such as LDL, lipoprotein(a) (Lp(a)), and triglyceride-rich lipoproteins. Evolocumab and alirocumab, monoclonal antibody proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors which lower LDL-C by approximately 60%, have emerged as important therapies for use in patients with ASCVD as well as familial hypercholesterolemia (FH). Bempedoic acid, an ATP citrate lyase inhibitor, is an oral medication recently approved that can lower LDL-C by approximately 18% alone and 38% when combined with ezetimibe. Inclisiran, a small-interfering RNA (siRNA) molecule which inhibits the translation of PCSK9, is the most recently FDA-approved LDL-C lowering medication, and can reduce LDL-C by approximately 50% with twice yearly subcutaneous dosing. The cardiovascular outcome trials for bempedoic acid and inclisiran are still on-going. Evinacumab, a monoclonal antibody which targets angiopoietin-like protein 3 (ANGPTL3), has been approved for use in patients with homozygous FH. SiRNAs and anti-sense oligonucleotides (ASO) facilitating selective inhibition of the production of targeted proteins including Lp(a) and ANGLPTL3 are active areas of clinical investigation.SummaryRecently several novel LDL-C lowering medications have been approved. New therapeutic targets have been identified and present additional means of lowering LDL-C and other atherogenic compounds for patients who remain at high ASCVD risk.

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

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

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