Cardiovascular disease(CVD) remains the largest cause of mortality worldwide. The development of new effective therapeutics is a major unmet need. Opening new doors to pathways previously considered “untargetable” are alternative therapeutic modalities, including RNA-based therapies which have the high-fidelity nature of complementary base-pairing of therapeutic and target. The use of RNA-based therapies is rapidly accelerating as evidenced by the number of clinical trials using this approach. Specifically, within the CVD space, RNA-based therapies are currently undergoing testing in several areas including those of lipid management, hypertension, HF, and amyloidosis.

Traditional small organic compound drugs target enzymes or receptors in the extracellular and/or intracellular space by affecting enzyme function or signaling, respectively. Pharmacological targeting of mRNA represents an emerging, innovative approach that operates upstream. mRNA-targeting drugs cross the cell membrane and are released into the cytoplasm, eventually blocking the mRNA translation of the proteins(Figure 1). Two major classes of agents have been developed: antisense oligonucleotides(ASO) and small interfering RNA(siRNAs). Early problems with their use have been overcome by conjugation with N-acetylgalactosamine, an adduct that targets their delivery to the primary site of action in the liver. The advantages of these agents include long dosing intervals of up to 6 months and the potential to regulate the abundance of any disease-related protein. Cardiovascular outcome and long-term safety with RNA-targeting drugs are still ongoing in large-scale clinical trials.

Figure 1. Mechanisms of mRNA degradation with RNA-based drugs (JACC 2020;76:563-79)

ASO: antisense oligonucleotide, mRNA = messenger RNA, RISC: RNA-induced silencing complex, RNase: ribonuclease