title: Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Merki
authors.forename: Mark
authors.initials: M
authors.lastname: Graham
authors.forename: Adam
authors.initials: A
authors.lastname: Taleb
authors.forename: Gregor
authors.initials: G
authors.lastname: Leibundgut
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yang
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Miller
authors.forename: Wuxia
authors.initials: W
authors.lastname: Fu
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.forename: Richard
authors.initials: R
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Willeit
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
mesh_terms: D000818:Animals; D053241:Apoprotein(a) / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D007668:Kidney / Q000473:pathology / Q000502:physiology; D018082:Kringles / Q000235:genetics; D017270:Lipoprotein(a) / Q000097:blood*; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009841:Oligonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: C558606:ASO 144367; D017270:Lipoprotein(a); D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D010743:Phospholipids; D014280:Triglycerides; D002784:Cholesterol; D053241:Apoprotein(a)