Apolipoprotein(a) messenger RNA (LPA mRNA)

Apolipoprotein(a) messenger RNA (LPA mRNA) is the primary transcript of the LPA gene (NCBI Gene: 4018), synthesized almost exclusively in hepatocytes. It serves as the template for the translation of apolipoprotein(a), a glycoprotein that covalently binds to apolipoprotein B-100 to form Lipoprotein(a) [Lp(a)] (UniProt: P08519). Elevated circulating levels of Lp(a) are a genetically determined, independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (Tsimikas et al., NEJM, 2020). Because Lp(a) levels are largely unaffected by statins or lifestyle modifications, LPA mRNA has emerged as a high-priority therapeutic target for RNA-based medicines. Drugs such as Pelacarsen (an antisense oligonucleotide) and Olpasiran (a small interfering RNA) are designed to bind to the LPA mRNA sequence, triggering its degradation and preventing the synthesis of the apolipoprotein(a) protein (O'Donoghue et al., NEJM, 2022). These therapies typically utilize N-acetylgalactosamine (GalNAc) conjugation to ensure specific delivery to the liver, minimizing systemic exposure and enhancing potency. Clinical trials have demonstrated that targeting LPA mRNA can reduce serum Lp(a) levels by over 90%, providing a potential breakthrough for reducing residual cardiovascular risk (Nissen et al., JAMA, 2023).

Other names

Apo(a) mRNALipoprotein(a) mRNALPA transcriptApolipoprotein(a) gene transcript

RNA-targeted inhibition of protein synthesis via antisense oligonucleotide-mediated RNase H cleavage or siRNA-mediated RNA-induced silencing complex (RISC) degradation of the LPA transcript.