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Review
. 2022 May;24(5):307-321.
doi: 10.1007/s11883-022-01007-9. Epub 2022 Apr 2.

RNA Therapeutics: the Next Generation of Drugs for Cardiovascular Diseases

Nada Bejar #  1 , Trinh T Tat #  1 , Daniel L Kiss  2   3   4   5
Affiliations
Review

RNA Therapeutics: the Next Generation of Drugs for Cardiovascular Diseases

Nada Bejar et al. Curr Atheroscler Rep. 2022 May.

Abstract

Purpose of review: RNA therapeutics are a new and rapidly expanding class of drugs to prevent or treat a wide spectrum of diseases. We discuss the defining characteristics of the diverse family of molecules under the RNA therapeutics umbrella.

Recent findings: RNA therapeutics are designed to regulate gene expression in a transient manner. For example, depending upon the strategy employed, RNA therapies offer the versatility to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. RNA therapies include antisense nucleotides, microRNAs and small interfering RNAs, RNA aptamers, and messenger RNAs. Further, we discuss the mechanism(s) by which different RNA therapies either reduce or increase the expression of their targets. We review the RNA therapeutics approved (and those in trials) to treat cardiovascular indications. RNA-based therapeutics are a new, rapidly growing class of drugs that will offer new alternatives for an increasing array of cardiovascular conditions.

Keywords: Antisense oligonucleotide therapeutics; Cardiovascular disease; RNA therapeutics; mRNA therapeutics; siRNA therapeutics.

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Conflict of interest statement

Dr. Kiss runs an externally funded lab (American Heart Association [20CDA35310329], and NIH [R35GM137819-02, -02S1, -02S2]) that is actively designing and testing different candidate RNA therapeutics, including some with possible applications in cardiovascular disease. All authors anticipate seeking appropriate intellectual property protection for promising candidates that emerge from the lab’s work. Dr. Kiss has patents planned for circular RNA therapeutics and an inducible stable HUVEC cell line. Further, Dr. Kiss serves as a consultant for the RNA Core at the Houston Methodist Research Institute. In addition, Dr. Kiss reports private stock for BioLife Solutions Inc. Dr. Bejar is named as a co-inventor on a provisional patent filing for a candidate RNA therapeutic (EFS ID: 44070986 pending). Dr. Tat has a patent planned for circular RNA therapeutics.

Figures

Fig. 1
Fig. 1
Mechanisms of action for selected RNA-based drugs to treat cardiovascular diseases. Top left: Mipomersen is an example of an ASO drug (red) which hybridizes to ApoB-100 mRNA and recruits RNase H1 to cleave the targeted mRNA, preventing apolipoprotein B production, which then reduces the synthesis of VLDL and LDL. Top right: Inclisiran as an siRNA therapy that targets PCSK9 mRNA. The targeting strand is incorporated into RISC complexes which then recognize the targeted mRNA and initiates its cleavage and degradation. This decreases the amount of PCSK9 protein produced, blocking the PCSK9-driven internalization and degradation of LDL receptors. The increased numbers of cell surface LDL receptors then remove more LDL from circulation thereby reducing bloodborne LDL levels. Bottom left: BT200 is an RNA aptamer designed to inhibit aberrant thrombus formation. This aptamer blocks the interaction between VWF (von Willebrand factor) and GP IIb/IIIa receptors on platelet membranes, triggering the blockage of platelet thrombus formation. Bottom right: AZD8601 is an mRNA therapy designed to increase angiogenesis. Optimized VEGF-A mRNAs are packaged in lipid nanoparticles (LNPs) which are endocytosed by the targeted host cells. The mRNA is then translated into VEGF-A protein which increases angiogenesis. Figure generated using BioRender.com
See this image and copyright information in PMC

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