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靶向脂蛋白(a):RNA疗法能否成为预防心血管疾病的下一步方案?

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

作者信息

Thau Henriette, Neuber Sebastian, Emmert Maximilian Y, Nazari-Shafti Timo Z

机构信息

Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), 13353, Berlin, Germany.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353, Berlin, Germany.

出版信息

Cardiol Ther. 2024 Mar;13(1):39-67. doi: 10.1007/s40119-024-00353-w. Epub 2024 Feb 21.

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.

摘要

众多遗传学和流行病学研究已证实脂蛋白(a)[Lp(a)]水平升高与心血管疾病之间存在关联。因此,降低Lp(a)水平被广泛认为是降低新发冠心病、中风和心力衰竭风险的一种有前景的策略。Lp(a)由一个与载脂蛋白A(apo[a])和载脂蛋白B-100共价连接的低密度脂蛋白样颗粒组成,这解释了其促血栓形成、促炎和促动脉粥样硬化特性。Lp(a)血清浓度由apo(a)异构体通过遗传方式决定,异构体越短,颗粒合成速率越高。迄今为止,尚无获批的有效降低Lp(a)水平的药物疗法。针对apo(a)表达的有前景的治疗方法包括基于RNA的药物,如pelacarsen、olpasiran、SLN360和lepodisiran,这些药物目前正处于临床试验阶段。在这篇综述中,我们详细概述了基于RNA的治疗方法,并讨论了专门设计用于降低Lp(a)水平从而降低心血管疾病风险的RNA疗法的最新进展和挑战。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3749/10899152/13df2d15b15f/40119_2024_353_Fig1_HTML.jpg

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