Targeting and delivery of microRNA-targeting antisense oligonucleotides in cardiovascular diseases

Abstract

Discovered three decades ago, microRNAs (miRNAs) are now recognized as key players in the pathophysiology of multiple human diseases, including those affecting the cardiovascular system. As such, miRNAs have emerged as promising therapeutic targets for preventing the onset and/or progression of several cardiovascular diseases. Anti-miRNA antisense oligonucleotides or "antagomirs" precisely block the activity of specific miRNAs and are therefore a promising therapeutic strategy to repress pathological miRNAs. In this review, we describe advancements in antisense oligonucleotide chemistry that have significantly improved efficacy and safety. Moreover, we summarize recent approaches for the targeted delivery of antagomirs to cardiovascular tissues, highlighting major advantages as well as limitations of viral (i.e., adenovirus, adeno-associated virus, and lentivirus) and non-viral (i.e., liposomes, extracellular vesicles, and polymer nanoparticles) delivery systems. We discuss recent preclinical studies that use targeted antagomir delivery systems to treat three major cardiovascular diseases (atherosclerosis, myocardial infarction, and cardiac hypertrophy, including hypertrophy caused by hypertension), highlighting therapeutic results and discussing challenges that limit clinical applicability.

Keywords: Antagomir; Cardiovascular diseases; Encapsulation; Targeted delivery; microRNA.

Figure 1.

Schematic representation of targeted antagomir delivery systems and administration routes. (Upper panel): Antagomirs (pink) are administered as non-encapsulated ASOs (A), are expressed from viral vectors (B), or are delivered by non-viral nanoparticle (NP) carriers (C). Some NP carriers can be loaded with plasmids (not shown) that express the antagomirs after cell entry. (A) Non-encapsulated antagomirs can be linked to functional groups such as ligands (e.g., N-acetylgalactosamine) that bind specific cell surface receptors or to cholesterol or cell-permeable peptides that enhance cell entry. Alternatively, photolabile “cages” can be linked to the antagomir nucleobases, allowing site-specific activation of the antagomir by illumination. (B) Antagomirs can also be expressed from viral vectors, typically adenoviruses (Ad), adeno-associated viruses (AAV), and lentiviruses (LV). In these cases, an expression cassette containing the antagomir sequence (pink) is inserted into the viral genome, potentially allowing long-term antagomir expression from within transduced cells. (C) Synthetic antagomirs (pink) or antagomir-encoding plasmids (not shown) can be incorporated within lipid-based NPs (e.g., extracellular vesicles (EVs), liposomes, or polymer-based NPs). Lower panel: Antagomirs are commonly administered via intravenous injection (D), subcutaneously (not shown), or by injection into the adventitia (E). Antagomirs can also be injected directly into the myocardium or applied to the epicardium using hydrogel scaffolds (F). Intracoronary administration (not shown) is also used to deliver antagomirs to the myocardium. This figure was partly generated using Servier Medical Art.