Antisense oligonucleotides (ASOs) are DNA fragments that bind to their complementary target mRNA via A-T, C-G base pairing. This triggers ribonuclease H (RNase H) activity leading to mRNA degradation, and other destabilising mechanisms, that result in reduced mRNA levels and inhibition of target protein synthesis.1
ASOs can be directed to the liver, where Lp(a) particles are mainly produced, through conjugation of the ASO with an N-acetylgalactosamine (GalNac) moiety which binds to the asialoglycoprotein receptor on the hepatic cell surface, thus facilitating entry of the ASO into the cell.
Pelacarsen (formerly AKCEA-APO(a)-LRx, ISIS 681257) is a GalNac ASO which targets mRNA for LPA, the gene that encodes for apolipoprotein(a) (apo(a)), a key component of Lp(a). In a phase 2a trial, pelacarsen reduced Lp(a) levels in a dose-dependent manner by 66% to 92% in participants with elevated lipoprotein(a) levels.2
View References
- Tselepis AD. Treatment of Lp(a): Is It the Future or Are We Ready Today? Curr Atheroscler Rep. 2023 Oct;25(10):679-689.
- Viney NJ, van Capelleveen JC, Geary RS et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016 Nov 5;388(10057):2239-2253.
