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Review
. 2021 May 1;36(3):256-263.
doi: 10.1097/HCO.0000000000000850.

RNA therapeutics for cardiovascular disease

Christian Boada  1   2 , Roman Sukhovershin  1 , Roderic Pettigrew  2   3 , John P Cooke  1
Affiliations
Review

RNA therapeutics for cardiovascular disease

Christian Boada et al. Curr Opin Cardiol. .

Abstract

Purpose of review: The development of mRNA vaccines against coronavirus disease 2019 has brought worldwide attention to the transformative potential of RNA-based therapeutics. The latter is essentially biological software that can be rapidly designed and generated, with an extensive catalog of applications. This review aims to highlight the mechanisms of action by which RNA-based drugs can affect specific gene targets and how RNA drugs can be employed to treat cardiovascular disease, with the focus on the therapeutics being evaluated in clinical trials. The recent advances in nanotechnology aiding the translation of such therapies into the clinic are also discussed.

Recent findings: There is a growing body of studies demonstrating utility of RNA for targeting previously 'undruggable' pathways involved in development and progression of cardiovascular disease. Some challenges in RNA delivery have been overcome thanks to nanotechnology. There are several RNA-based drugs to treat hypercholesterolemia and myocardial infarction which are currently in clinical trials.

Summary: RNA therapeutics is a rapidly emerging field of biotherapeutics based upon a powerful and versatile platform with a nearly unlimited capacity to address unmet clinical needs. These therapeutics are destined to change the standard of care for many diseases, including cardiovascular disease.

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Conflict of interest statement

Conflicts of interest

Dr. Cooke is an inventor of patents, assigned to Stanford University and licensed to Cooke’s company, which protect the use of mRNA telomerase for cellular rejuvenation. Dr. Sukhovershin has filed invention disclosures with Houston Methodist Hospital regarding the manufacturing and testing of mRNA constructs, which intellectual property has been licensed to VGXI Inc. The remaining authors have no conflicts of interest.

Figures

Figure 1.
Figure 1.. Mechanisms of Action for RNA Therapeutics.
miRNA and siRNA use the RISC (RNA-induced silencing complex) to degrade the target gene’s complementary mRNA strands or to prevent protein translation, thereby downregulating the expression of a given target gene. Antisense Oligonucleotides (ASOs) rely on various mechanisms to inhibit translation of a target mRNA sequence, which may include steric blocking and ribonuclease H decay of pre-mRNA. Conversely, therapeutic mRNA accesses the cytoplasmic translational machinery to express a protein that is useful in treating a disease. Silencing the expression of endogenous mRNA has proved useful in the treatment of hypercholesterolemia, while expression of target proteins has proven effective in the vaccines for COVID-19, and of promise in the treatment of myocardial infarction (AZD8601 - VEGF). Created with BioRender.com
Figure 2.
Figure 2.. Delivery Platforms for nucleic acid therapeutics.
RNA often requires a delivery vehicle to be injected. One approach to deliver nucleic acid therapies are viral vectors, such as adeno-associated virus. A non-viral approach is to use liposome encapsulation using nanoparticles. These nanoparticles are typically self-assembled lipid vesicles surrounding the nucleic acids. This latter strategy has been used for Pfizer and Moderna COVID-19 vaccines and treatments for myocardial infarction currently in clinical trials. Created with BioRender.com
Figure 3.
Figure 3.. RNA Liposome Structure and Surface Modifications.
The basic structure of a lipid RNA particle consists of phospholipids and cationic phospholipids and RNA. The cationic (net positive charge) of some phospholipids drives interaction with the negative phosphate backbone of RNA, effectively encapsulating it; other lipids complete the liposome formation in a structure commonly known as a “lipoplex.” At the surface, liposomes can be functionalized with various modifications that alter their distribution throughout the body. Some of these modifications include polymer coating of the surface lipids (e.g., polyethylene glycol or PEG), the inclusion of membrane or recombinant proteins (for targeting or transmigration) in the bilayer, and covalent modifications with fluorophores for imaging. Created with BioRender.com
See this image and copyright information in PMC

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