Molecular Therapies in Cardiovascular Diseases: Small Interfering RNA in Atherosclerosis, Heart Failure, and Hypertension

Abstract

Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through RNA interference. In the cardiovascular (CV) field, several siRNAs have been developed in the last decade. Inclisiran has been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) circulating levels with a reassuring safety profile, also in older patients, by hampering proprotein convertase subtilisin/kexin type 9 (PCSK9) production. Olpasiran, directed against apolipoprotein(a) mRNA, prevents the assembly of lipoprotein(a) [Lp(a)] particles, a lipoprotein linked to an increased risk of ischemic CV disease and heart valve damage. Patisiran, binding transthyretin (TTR) mRNA, has demonstrated an ability to improve heart failure and polyneuropathy in patients with TTR amyloidosis, even in older patients with wild-type form. Zilebesiran, designed to reduce angiotensinogen secretion, significantly decreases systolic and diastolic blood pressure (BP). Thanks to their effectiveness, safety, and tolerability profile, and with a very low number of administrations in a year, thus overcoming adherence issues, these novel drugs are the leaders of a new era in molecular therapies for CV diseases.

Keywords: amyloidosis; atherosclerosis; heart failure; hypertension; inclisiran; lepodisiran; olpasiran; patisiran; small interfering RNA; zilebesiran.

Figure 1

Mechanism of hepatic delivery and RNA interference of siRNAs. All the siRNAs discussed in the text exert their action within the liver, but they use different delivery mechanisms. Inclisiran, olpasiran, lepodisiran, ARO-APOC3, and zilebesiran are administered subcutaneously, covalently linked to a GalNAc “trident” that binds with high affinity to the ASGPR on the hepatocyte surface. Hence, they gain endosomal entry into the cell and dissociate from GalNAc and ASGPR inside the endosome. Patisiran is administered intravenously, and it is formulated as an encapsulated lipid nanoparticle consisting of a largely hydrophobic core with inverted micelles of lipids and an outer coating of PEG lipids and cholesterol-acquiring ApoE from circulating VLDL and IDL. Patisiran nanoparticle coated by ApoE binds to the LDLR on the hepatocyte surface, and internalization by endocytosis ensues. Once inside the cell, siRNAs bind a specific protein complex and form the RISC, where they are separated into two strands: one of these strands (the “guide” strand) binds its target, a specific mRNA sequence, and leads to its degradation, preventing RNA translation and inhibiting corresponding protein synthesis. The specific targets are the following: PCSK9 for inclisiran, Lp(a) for olpasiran (and lepodisiran), APOC3 for ARO-APOC3, TTR for patisiran (and vutrisiran), and AGT for zilebesiran. AGT: angiotensinogen; APOC3: apolipoprotein C-III; ApoE: apolipoprotein E; ASGPR: asialoglycoprotein receptor; GalNAc: N-acetyl-galactosamine; IDL: intermediate-density lipoprotein; LDLR: low-density lipoprotein receptor; Lp(a): lipoprotein(a); PCSK9: proprotein convertase subtilisin/kexin type 9; PEG: polyethylene glycol; RISC: RNA-induced silencing complex; siRNA: small interfering RNA; TTR: transthyretin; VLDL: very low-density lipoprotein.