APOC3 siRNA and ASO therapy for dyslipidemia.

IF 2.6 3区医学 Q3 ENDOCRINOLOGY & METABOLISM Current Opinion in Endocrinology & Diabetes and Obesity Pub Date : 2024-04-01 Epub Date: 2024-02-09 DOI:10.1097/MED.0000000000000857

Jasmine Chebli, Miriam Larouche, Daniel Gaudet

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Abstract

Purpose of review: The aim of this review is to present the clinical indications of apolipoprotein C-III (apoC3) inhibition in the therapeutic arsenal for the treatment of lipid disorders and associated risks and to compare the most advanced modalities of apoC3 inhibition currently available or in development, specifically APOC3 antisense oligonucleotides (ASO) and small interfering RNA (siRNA).

Recent findings: ApoC3 inhibition significantly decreases triglyceride levels by mechanisms coupling both lipoprotein lipase (LPL) upregulation and LPL-independent mechanisms. The main apoC3 inhibitors in advanced clinical development are the GalNAc-ASO olezarsen and the GalNAc-siRNA plozasiran. Clinical studies conducted with volanesorsen, the olezarsen precursor, showed a favorable effect on hepatic steatosis (nonalcoholic fatty liver disease, NAFLD). Olezarsen does not appear to be associated with the main side effects attributed to volanesorsen including thrombocytopenia. Plozasiran is in advanced clinical development and requires subcutaneous injection every 3 months and present to-date an efficacy and safety profile comparable to that of the monthly ASO.

Summary: Inhibition of apoC3 is effective across all the spectrum of hypertriglyceridemia, might have a favorable effect on hepatic steatosis (NAFLD) and the effect of apoC3 inhibition on cardiovascular risk is not limited to its effect on plasma triglycerides. APOC3 GalNAc-conjugated ASO and siRNA are both effective in decreasing plasma apoC3 and triglyceride levels.

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APOC3 siRNA 和 ASO 治疗血脂异常。

综述目的：本综述旨在介绍载脂蛋白 C-III (apoC3)抑制剂在治疗血脂紊乱和相关风险方面的临床适应症，并比较目前可用或正在开发的最先进的载脂蛋白 C3 抑制方式，特别是 APOC3 反义寡核苷酸 (ASO) 和小干扰 RNA (siRNA)：最新研究结果：通过脂蛋白脂肪酶（LPL）上调机制和 LPL 依赖性机制，载脂蛋白 C3 抑制剂可显著降低甘油三酯水平。处于临床开发后期的载脂蛋白 C3 抑制剂主要是 GalNAc-ASO olezarsen 和 GalNAc-siRNA plozasiran。对olezarsen前体volanesorsen进行的临床研究显示，它对肝脏脂肪变性（非酒精性脂肪肝）有良好的效果。Olezarsen 似乎与 volanesorsen 的主要副作用（包括血小板减少）无关。小结：抑制载脂蛋白C3对所有高甘油三酯血症都有效，可能对肝脂肪变性（非酒精性脂肪肝）产生有利影响，而且抑制载脂蛋白C3对心血管风险的影响不仅限于对血浆甘油三酯的影响。APOC3 GalNAc 结合的 ASO 和 siRNA 都能有效降低血浆载脂蛋白 C3 和甘油三酯水平。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current Opinion in Endocrinology & Diabetes and Obesity ENDOCRINOLOGY & METABOLISM-

CiteScore

5.80

自引率

3.10%

发文量

128

审稿时长

6-12 weeks

期刊介绍： Current Opinion in Endocrinology, Diabetes and Obesity delivers a broad-based perspective on the most recent and exciting developments in the field from across the world. Published bimonthly and featuring twelve key topics – including androgens, gastrointestinal hormones, diabetes and the endocrine pancreas, and neuroendocrinology – the journal’s renowned team of guest editors ensure a balanced, expert assessment of the recently published literature in each respective field with insightful editorials and on-the-mark invited reviews.

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