The first antisense drug targeting apo(a) cuts Lp(a) by up to 25% and oxidized phospholipids by up to 92.5% in mice, a foundational study (J Am Coll Cardiol 2011)

Original title: Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice

J Am Coll Cardiol · 12 April 2011 · 8

Merki E, Graham M, Taleb A, Leibundgut G, Yang X, Miller ER, Fu W, Mullick AE, Lee R, Willeit P, Crooke RM, Witztum JL et al.

This study tested whether an antisense oligonucleotide (ASO 144367) targeting the kringle IV type 2 (KIV-2) repeat of apolipoprotein(a) [apo(a)] lowers Lp(a) in three transgenic mouse models: 8K-apo(a) mice, 8K-Lp(a) mice (expressing 8K apo(a) plus human apoB-100), and 12K-apo(a) mice, treated for 4-6 weeks. ASO 144367 significantly reduced Lp(a) by 24.8% and apo(a) by 19.2% in 8K-Lp(a) mice, apo(a) by 30.0% in 8K-apo(a) mice, and apo(a) by 86% in 12K-apo(a) mice; it also reduced oxidized phospholipids on apoB by 22.4% and on apo(a) by 19.9%, 22.1%, and 92.5% in the respective models (P<0.004 or less for all), with no changes seen with control ASO or saline. The findings document the first specific therapy for lowering apo(a)/Lp(a) and their associated oxidized phospholipids, with a more potent effect in mice expressing apo(a) with more KIV-2 repeats, suggesting ASOs targeting KIV-2 could effectively lower Lp(a) in humans.

Original abstract

Objectives: This study sought to assess whether an antisense oligonucleotide (ASO) directed to apolipoprotein (a) [apo(a)] reduces apo(a) and lipoprotein (a) [Lp(a)] levels in transgenic mouse models.

Background: Elevated Lp(a) is a causal, independent, genetic risk factor for cardiovascular disease and myocardial infarction. Effective therapies to specifically lower plasma Lp(a) levels are lacking.

Methods: Three transgenic mouse models were utilized: 8K-apo(a) mice expressing 8 kringle IV (KIV) repeats with a single copy of KIV-2; 8K-Lp(a) mice expressing both the 8K apo(a) plus human apolipoprotein B-100; and 12K-apo(a) mice expressing a 12K apo(a) with 3 KIV-2 repeats. The mice were treated intraperitoneally with saline, a control ASO, or ASO 144367 directed to KIV-2 for 4 to 6 weeks. Apo(a), Lp(a), and oxidized phospholipids present on human apoB (OxPL/h-apoB) or apo(a) [OxPL/apo(a)] were measured at baseline and on and off therapy.

Results: ASO 144367 significantly reduced Lp(a) by 24.8% in 8K-Lp(a) mice, and reduced apo(a) levels by 19.2% in 8K-Lp(a) mice, 30.0% in 8K-apo(a) mice, and 86% in 12K-apo(a) mice; ASO 144367 also significantly reduced OxPL/apoB 22.4% in 8K-Lp(a) mice, and OxPL/apo(a) levels by 19.9% in 8K-Lp(a) mice, 22.1% in 8K-apo(a) mice, and 92.5% in 12K-apo(a) mice (p < 0.004, or less, for all). No significant changes occurred in Lp(a), apo(a), OxPL/apoB, or OxPL/apo(a) levels with control ASO or saline.

Conclusions: This study documents the first specific therapy, to our knowledge, for lowering apo(a)/Lp(a) levels and their associated OxPL. A more potent effect was documented in mice expressing apo(a) with multiple KIV-2 repeats. Targeting liver expression of apo(a) with ASOs directed to KIV-2 repeats may provide an effective approach to lower elevated Lp(a) levels in humans.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.