Hyperlipoproteinemia(a): the role of antisenseoligonucleotides in reduction of lipoprotein(a) level. Literature review

The literature review is devoted to a relevant problem of correction of elevated level of lipoprotein(a) (LP(a)) which is a risk factor (RF) for atherosclerotic cardiovascular diseases (ACVD) and demonstrates a stability to action of existing lipid‑lowering drugs (LLD) due to genetic determination of apolipoprotein(a) (apo(a)), a structural component of LP(a) molecule. Since human lipid metabolism is regulated by many genes, the majority of them, in particular, apo(a) gene can be potential targets for innovative antisense therapy, a method of treatment based on reduction of synthesis of LP(a) involved in the development of ACVD through inhibition of apo(a) matrix ribonucleic acid (mRNA) translation due to connection with complementary short sequences called antisense oligonucleotides (ASO). Update insights into the structure and pathophysiological role of LP(a) in atherothrombosis, a necessity of hyperlipoproteinemia(a) correction caused by its proatherosclerotic and prothrombotic effects are given. A focus was made on innovative LLD with high potential in treatment of ACVD and correction of their risk factors, particularly on ASO capable of blocking a translation of apo(a) mRNA. Principal mechanisms of ASO action, the ways of their delivery to mRNA targets are presented. The data of studies on LP(a) reduction with mipomersen, pelacarsen, SLN360 agent, olpasiran and lepodisiran are presented. It is emphasized that despite the efficacy of enumerated ASO in LP(a) reduction, there are unknown long­­term consequences of its intensive reduction, particularly an influence on cardiovascular events and the functional state of organs and their systems in different diseases. The only ASO drug approved by the US Food and Drug Administration is mipomersen recommended for correction of low­­density lipoprotein cholesterol and LP(a) levels due to its ability to block apolipoprotein B­­100 synthesis. In Europe mipomersen was not registered because of its unfavorable safety profile. Thus, despite the prospects for developing new drugs based on antisense technologies, many questions remain about their efficacy and safety, especially for LLD intended for long­­term use.