Recent updates on therapeutic targeting of lipoprotein(a) with RNA interference.

IF 2 4区 医学 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS Current Opinion in Cardiology Pub Date : 2024-07-01 Epub Date: 2024-03-26 DOI:10.1097/HCO.0000000000001144
Aravind Sekhar, Ashani Kuttan, Richard A Lange
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Abstract

Purpose of review: RNA interference (RNAi)-based therapies that target specific gene products have impacted clinical medicine with 16 FDA approved drugs. RNAi therapy focused on reducing plasma lipoprotein(a) [Lp(a)] levels are under evaluation.

Recent findings: RNAi-based therapies have made significant progress over the past 2 decades and currently consist of antisense oligonucleotides (ASO) and small interfering RNA (siRNA). Chemical modification of the RNA backbone and conjugation of siRNA enables efficient gene silencing in hepatocytes allowing development of effective cholesterol lowering therapies. Multiple lines of evidence suggest a causative role for Lp(a) in atherosclerotic cardiovascular disease, and recent analyses indicate that Lp(a) is more atherogenic than low density lipoprotein- cholesterol (LDL-C). These findings have led to the 'Lp(a) hypothesis' that lowering Lp(a) may significantly improve cardiovascular outcomes. Four RNAi-based drugs have completed early phase clinical trials demonstrating >80% reduction in plasma Lp(a) levels. Phase 3 clinical trials examining clinical outcomes with these agents are currently underway.

Summary: Currently, four RNAi-based drugs have been shown to be effective in significantly lowering plasma Lp(a) levels. Clinical outcome data from phase 3 trials will evaluate the Lp(a) hypothesis.

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利用 RNA 干扰对脂蛋白(a)进行靶向治疗的最新进展。
目的:以 RNA 干扰(RNAi)为基础、靶向特定基因产物的疗法已影响到临床医学,美国食品及药物管理局已批准 16 种药物。目前正在对重点降低血浆脂蛋白(a)[Lp(a)]水平的 RNAi 疗法进行评估:基于 RNAi 的疗法在过去 20 年中取得了重大进展,目前包括反义寡核苷酸 (ASO) 和小干扰 RNA (siRNA)。通过对 RNA 主干进行化学修饰并连接 siRNA,可在肝细胞中实现高效的基因沉默,从而开发出有效的降低胆固醇疗法。多种证据表明,脂蛋白(a)在动脉粥样硬化性心血管疾病中具有致病作用,最近的分析表明,脂蛋白(a)比低密度脂蛋白胆固醇(LDL-C)更容易导致动脉粥样硬化。这些发现提出了 "脂蛋白(a)假说",即降低脂蛋白(a)可显著改善心血管疾病的预后。目前已有四种基于 RNAi 的药物完成了早期临床试验,结果显示血浆脂蛋白(a)水平降低了 80% 以上。摘要:目前,已有四种基于 RNAi 的药物被证明能有效大幅降低血浆脂蛋白(a)水平。第三阶段试验的临床结果数据将对脂蛋白(a)假说进行评估。
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来源期刊
Current Opinion in Cardiology
Current Opinion in Cardiology 医学-心血管系统
CiteScore
4.20
自引率
4.30%
发文量
78
审稿时长
6-12 weeks
期刊介绍: ​​​​​​Current Opinion in Cardiology is a bimonthly publication offering a unique and wide ranging perspective on the key developments in the field. Each issue features hand-picked review articles from our team of expert editors. With fourteen disciplines published across the year – including arrhythmias, molecular genetics, HDL cholesterol and clinical trials – every issue also contains annotated reference detailing the merits of the most important papers.
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