RNA interference therapy in cardiology: will new targets improve therapeutic goals?

Abstract

The discovery of RNA interference in 1998 opened avenues for the manipulation of gene expression, leading to the development of small interfering RNA (siRNA) drugs. Patisiran, the first FDA-approved siRNA medication, targets hereditary transthyretin amyloidosis with polyneuropathy. Givosiran, lumasiran and nedosiran further expand siRNA applications in treating rare genetic diseases, demonstrating positive outcomes. In cardiology, inclisiran, approved for hypercholesterolaemia, showcases sustained reductions in LDL cholesterol levels. However, ongoing research aims to establish its impact on cardiovascular outcomes. Lipoprotein(a), an independent risk factor for atherosclerotic cardiovascular disease, has become a focus of siRNA therapies, precipitating the development of specific siRNA drugs like olpasiran, zerlasiran and lepodisiran, with promising reductions in lipoprotein(a) levels. Research to assess the effectiveness of these medications in reducing events is currently under way. Zodasiran and plozasiran address potential risk factors for cardiovascular diseases, targeting triglyceride-rich lipoproteins. Zilebesiran, which targets hepatic angiotensinogen mRNA, has demonstrated a dose-related reduction in serum angiotensinogen levels, thereby lowering blood pressure in patients with systemic arterial hypertension. The evolving siRNA methodology presents a promising future in cardiology, with ongoing studies assessing its effectiveness in various conditions. In the future, larger studies will provide insights into improvements in cardiovascular outcomes, long-term safety and broader applications in the general population. This review highlights the historical timeline of the development of siRNA-based drugs, their clinical indications, potential side-effects and future perspectives.

Keywords: dyslipidaemia; small interfering RNA; systemic arterial hypertension.

Figure 1

Mechanism of action of small interference (siRNA) molecules. 1 – siRNA delivery methods in hepatocytes: (a) lipid nanoparticles enter the cell by endocytosis, releasing siRNA cargo into the cytosol. (b) Conjugated N-acetylgalactosamine (GalNAc) binds to asialoglycoprotein receptor expressed on hepatocyte membrane; the complex undergoes a process of internalization in lysosomes with subsequent release of its siRNA cargo. 2 – siRNA associates with Argonaute2 (Ago2) enzyme to form the RNA-induced silencing complex (RISC), being cleaved into a single strand and becoming active. 3 – The strand within the complex serves as a guide for the enzyme to cleave the target region in the messenger RNA (mRNA), silencing its effect.

Figure 2

Historical timeline of development of siRNA-based drugs.