Angiopoietin-like 3 inhibition and the liver: less is more?

IF 3.8 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in lipidology Pub Date : 2023-12-01 Epub Date: 2023-10-11 DOI:10.1097/MOL.0000000000000898

Reindert F Oostveen, G Kees Hovingh, Erik S G Stroes

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Abstract

Purpose of review: The aim of this study was to discuss the potential mechanisms and implications of the opposing liver safety results from recent angiopoietin-like 3 (ANGPTL3) inhibition studies.

Recent findings: The clinical development of vupanorsen, a N-acetylgalactosamine (GalNAc) antisense targeting hepatic ANGPTL3, was recently discontinued due to a significant signal of liver transaminase increase. Vupanorsen elicited a dose-dependent increase in hepatic fat fraction up to 75%, whereas the small interfering RNA (siRNA) ARO-ANG3, has reported preliminary evidence of a dose-dependent decrease in hepatic fat fraction up to 30%.

Summary: ANGPTL3 inhibition is an attractive therapeutic target to reduce all apoB-containing lipoproteins. The discrepancy in liver signal results between the antisense and siRNA approach may be explained by the level of target inhibition. An alternative explanation may relate to off-target effects of vupanorsen, which have a molecule- and/or platform-specific origin. For intrahepatic strategies, highly potent ANGPTL3 inhibition will for now require special attention for liver safety.

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血管生成素样3抑制与肝脏：少即是多？

综述目的：本研究的目的是讨论最近血管生成素样3（ANGPTL3）抑制研究的潜在机制和对肝脏安全性的影响。最近的发现：vupanorsen是一种靶向肝脏ANGPTL3的N-乙酰氨基半乳糖（GalNAc）反义药物，由于肝脏转氨酶升高的显著信号，其临床开发最近停止。Vupanorsen引起肝脂肪分数的剂量依赖性增加高达75%，而小干扰RNA（siRNA）ARO-ANG3已报道初步证据表明肝脂肪分数呈剂量依赖性减少高达30%。总结：ANGPTL3抑制是一个有吸引力的治疗靶点，可减少所有含载脂蛋白B的脂蛋白。反义和siRNA方法之间肝信号结果的差异可以通过靶抑制水平来解释。另一种解释可能与vupanorsen的脱靶效应有关，后者具有分子和/或平台特异性起源。对于肝内策略，高效的ANGPTL3抑制目前需要特别关注肝脏安全性。

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 lipidology 医学-内分泌学与代谢

CiteScore

6.70

自引率

4.50%

发文量

审稿时长

6-12 weeks

期刊介绍： With its easy-to-digest reviews on important advances in world literature, Current Opinion in Lipidology offers expert evaluation on a wide range of topics from six key disciplines including nutrition and metabolism, genetics and molecular biology, and hyperlipidaemia and cardiovascular disease. Published bimonthly, each issue covers in detail the most pertinent advances in these fields from the previous year. This is supplemented by a section of Bimonthly Updates, which deliver an insight into new developments at the cutting edge of the disciplines covered in the journal.