Abstract
The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled. Initially, the therapeutic approaches to reduce circulating levels of PCSK9 were focused on the use of monoclonal antibodies. To that effect, evolocumab and alirocumab, two human monoclonal antibodies directed against PCSK9, given on a background of statin therapy, have been shown to markedly decrease LDL-C levels and significantly reduce cardiovascular risk. The small interfering RNA (siRNA) molecules have been used recently to target the hepatic production of PCSK9. siRNA interferes with the expression of specific genes with complementary nucleotide sequences by affecting the degradation of mRNA post-transcription, thus preventing translation. Inclisiran is a long-acting, synthetic siRNA directed against PCSK9 and it has been shown to significantly decrease hepatic production of PCSK9 and cause a marked reduction in LDL-C levels. This review aims to present and discuss the current clinical and scientific evidence pertaining to inclisiran, which is a new promising agent in the management of hypercholesterolemia.
Highlights
Cardiovascular disease (CVD) is the number one cause of death worldwide
Hypercholesterolemia is a major known risk factor for cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) lowering has been unequivocally shown to cause a significant reduction in cardiovascular risk in both primary and secondary prevention [2,3]
The small interfering RNA (siRNA) molecules follow the natural pathway of RNA interference (RNAi) by binding intracellularly to the RNA-induced silencing complex (RISC), enabling it to cleave messenger RNA molecules encoding proprotein convertase subtilisin-kexin type 9 (PCSK9) [19]
Summary
Cardiovascular disease (CVD) is the number one cause of death worldwide. An estimated. There is considerable variability in individual responses to statins [6] and many individuals at risk for CVD fail to achieve LDL-C goals [7,8]. Evolocumab and alirocumab, two human monoclonal antibodies directed against PCSK9, given on a background of statin therapy, have been shown to markedly decrease LDL-C levels and significantly reduce cardiovascular risk [14,15]. Molecule, which targets the hepatic production of PCSK9 and is currently under investigation for its LDL-C lowering effect and potential for cardiovascular risk reduction. Long double-stranded RNA induces an interferon response, which contributes to the antiviral defense. This interferon response prompts a generalized shutdown of protein synthesis. SiRNA interferes with the expression of specific genes with complementary nucleotide sequences by affecting the degradation of mRNA post-transcription, preventing translation [18]
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