RNA therapeutics
Mipomersen cuts Lp(a) by about 75% in transgenic mice, an early study establishing the antisense drug's mechanism (Circulation 2008)
Original 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
This study tested the antisense oligonucleotide mipomersen, directed against human apoB-100 mRNA, in transgenic mice expressing human apoB-100 alone or with human apo(a) to form genuine Lp(a) particles, treated for 11 weeks and followed 10 weeks off therapy. Mipomersen significantly reduced plasma apoB-100 in both mouse groups, and in Lp(a) mice reduced Lp(a) levels by approximately 75% from baseline (P<0.0001), with no effect on apo(a) levels or hepatic apo(a) mRNA expression. Oxidized phospholipids on apoB-100, much higher at baseline in Lp(a) mice than apoB-only mice (P<0.0001), also decreased over time with mipomersen, while the control antisense oligonucleotide had no effect. The findings show mipomersen substantially reduces Lp(a) and its associated oxidized phospholipids by limiting apoB-100 availability for Lp(a) assembly, suggesting a potential therapeutic approach for humans.
Original 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.
Methods And 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.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.