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

J Am Coll Cardiol. 2011 Apr 12;57(15):1611-21. doi: 10.1016/j.jacc.2010.10.052.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoprotein(a) / blood*
  • Apoprotein(a) / genetics
  • Apoprotein(a) / metabolism
  • Cholesterol / blood
  • Kidney / pathology
  • Kidney / physiology
  • Kringles / genetics
  • Lipoprotein(a) / blood*
  • Liver / metabolism
  • Liver / pathology
  • Liver / physiology
  • Mice
  • Mice, Transgenic
  • Oligonucleotides / pharmacology*
  • Oligonucleotides, Antisense / pharmacology*
  • Oxidation-Reduction
  • Phospholipids / metabolism
  • Triglycerides / blood


  • ASO 144367
  • Lipoprotein(a)
  • Oligonucleotides
  • Oligonucleotides, Antisense
  • Phospholipids
  • Triglycerides
  • Cholesterol
  • Apoprotein(a)