title: Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice.
abstract: BACKGROUND
  Lipoprotein (a) [Lp(a)] is a genetic cardiovascular risk factor that preferentially binds oxidized phospholipids (OxPL) in plasma. There is a lack of therapeutic agents that reduce plasma Lp(a) levels.
  
  
  RESULTS
  Transgenic mice overexpressing human apolipoprotein B-100 (h-apoB-100 [h-apoB mice]) or h-apoB-100 plus human apo(a) to generate genuine Lp(a) particles [Lp(a) mice] were treated with the antisense oligonucleotide mipomersen directed to h-apoB-100 mRNA or control antisense oligonucleotide for 11 weeks by intraperitoneal injection. Mice were then followed up for an additional 10 weeks off therapy. Lp(a) levels [apo(a) bound to apoB-100] and apo(a) levels ["free" apo(a) plus apo(a) bound to apoB-100] were measured by chemiluminescent enzyme-linked immunoassay and commercial assays, respectively. The content of OxPL on h-apoB-100 particles (OxPL/h-apoB) was measured by capturing h-apoB-100 in microtiter wells and detecting OxPL by antibody E06. As expected, mipomersen significantly reduced plasma h-apoB-100 levels in both groups of mice. In Lp(a) mice, mipomersen significantly reduced Lp(a) levels by approximately 75% compared with baseline (P<0.0001) but had no effect on apo(a) levels or hepatic apo(a) mRNA expression. OxPL/h-apoB levels were much higher at baseline in Lp(a) mice compared with h-ApoB mice (P<0.0001) but decreased in a time-dependent fashion with mipomersen. There was no effect of the control antisense oligonucleotide on lipoprotein levels or oxidative parameters.
  
  
  CONCLUSIONS
  Mipomersen significantly reduced Lp(a) and OxPL/apoB levels in Lp(a) mice. The present study demonstrates that h-apoB-100 is a limiting factor in Lp(a) particle synthesis in this Lp(a) transgenic model. If applicable to humans, mipomersen may represent a novel therapeutic approach to reducing Lp(a) levels and their associated OxPL.
authors.affiliation: University of California San Diego, La Jolla, CA 92093-0682, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Merki
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Miller
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.forename: Robert E
authors.initials: RE
authors.lastname: Pitas
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism*; D001054:Apolipoproteins A / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D017270:Lipoprotein(a) / Q000378:metabolism*; D008315:Malondialdehyde / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009841:Oligonucleotides / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
chemical_list: D053299:Apolipoprotein B-100; D001054:Apolipoproteins A; D001323:Autoantibodies; D017270:Lipoprotein(a); D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D010743:Phospholipids; D012333:RNA, Messenger; D014280:Triglycerides; D008315:Malondialdehyde; D002784:Cholesterol; C524142:mipomersen