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The Role of RNA-Targeted Therapeutics to Reduce ASCVD Risk: What Have We Learned Recently?

  • Coronary Heart Disease (S. Virani and S. Naderi, Section Editors)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

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.

Summary

RNA-targeted therapies are being extensively tested for dyslipidemia treatment with promising results.

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Funding

RDS is the recipient of a scholarship from Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico, Brazil, (CNPq) #303734/2018-3.

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Authors and Affiliations

  1. Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Av. Dr. Enéas C. Aguiar 44 CEP, São Paulo, SP, -05403-900, Brazil

    Marcio H. Miname, Viviane Z. Rocha & Raul D. Santos

  2. Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo, Brazil

    Raul D. Santos

Authors
  1. Marcio H. Miname
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  2. Viviane Z. Rocha
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  3. Raul D. Santos
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Contributions

MHM, VZR, and RDS have reviewed the literature and drafted the manuscript.

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Correspondence to Raul D. Santos.

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Conflict of Interest

MHM has received honoraria related to speaker activities from Amgen and EMS.

VZR has received honoraria related to speaker activities from Ache, Amgen, Novo Nordisk, and Sanofi.

RDS has received honoraria related to consulting, research, and/or speaker activities from Abbott, Ache, Amgen, AstraZeneca, Esperion, EMS, Getz Pharma, Kowa, Libbs, Novo Nordisk, Novartis, Merck, MSD, Pfizer, PTC Therapeutics, and Sanofi.

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This article is part of the Topical Collection on Coronary Heart Disease

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Miname, M.H., Rocha, V.Z. & Santos, R.D. The Role of RNA-Targeted Therapeutics to Reduce ASCVD Risk: What Have We Learned Recently?. Curr Atheroscler Rep 23, 40 (2021). https://doi.org/10.1007/s11883-021-00936-1

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