Small non-coding RNA therapeutics for cardiovascular disease

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Abstract

Novel bio-therapeutic agents that harness the properties of small, non-coding nucleic acids hold great promise for clinical applications. These include antisense oligonucleotides that inhibit messenger RNAs, microRNAs (miRNAs), or long non-coding RNAs; positive effectors of the miRNA pathway (short interfering RNAs and miRNA mimics); or small RNAs that target proteins (i.e. aptamers). These new therapies also offer exciting opportunities for cardiovascular diseases and promise to move the field towards more precise approaches based on disease mechanisms. There have been substantial advances in developing chemical modifications to improve the in vivo pharmacological properties of antisense oligonucleotides and reduce their immunogenicity. Carrier methods (e.g. RNA conjugates, polymers, and lipoplexes) that enhance cellular uptake of RNA therapeutics and stability against degradation by intracellular nucleases are also transforming the field. A number of small non-coding RNA therapies for cardiovascular indications are now approved. Moreover, there is a large pipeline of therapies in clinical development and an even larger list of putative therapies emerging from pre-clinical studies. Progress in this area is reviewed herein along with the hurdles that need to be overcome to allow a broader clinical translation.

Graphical Abstract

Graphical abstract

Types of small non-coding RNA therapeutics (left panel); some of the methods for in vivo delivery (centre); and routes for administration to the heart (right). ASO, antisense oligonucleotides; GalNAc, N-acetylgalactosamine; LNPs, lipid nanoparticles; miRNAs, microRNAs; siRNA, short interfering RNAs.

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Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Fernando P Polack, Stephen J. Thomas, Nicholas R.E. Kitchin … (2023)

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)

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Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Lindsey Baden, Hana El Sahly, Brandon Essink … (2020)

Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)

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MicroRNAs: genomics, biogenesis, mechanism, and function.

David Bartel (2004)

MicroRNAs (miRNAs) are endogenous approximately 22 nt RNAs that can play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

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Author and article information

Contributors

Ajay M Shah:

ORCID: https://orcid.org/0000-0002-6547-0631

Mauro Giacca:

ORCID: https://orcid.org/0000-0003-2927-7225

Journal

Journal ID (nlm-ta): Eur Heart J

Journal ID (iso-abbrev): Eur Heart J

Journal ID (publisher-id): eurheartj

Title: European Heart Journal

Publisher: Oxford University Press (US )

ISSN (Print): 0195-668X

ISSN (Electronic): 1522-9645

Publication date Collection: 14 November 2022

Publication date (Electronic): 15 September 2022

Publication date PMC-release: 15 September 2022

Volume: 43

Issue: 43 , Focus Issue on Vascular Biology and Medicine

Pages: 4548-4561

Affiliations

King’s College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine and Sciences , The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK

Author notes

Corresponding authors. Emails: ajay.shah@ 123456kcl.ac.uk (A.M.S.), mauro.giacca@ 123456kcl.ac.uk (M.G.)

Conflicts of interest: A.M.S. is an adviser to Forcefield Therapeutics and CYTE—Global Network for Clinical Research and sits on the Board of Heqet Therapeutics. M.G. is founder, consultant, member of the board, and equity holder in Purespring Therapeutics, Forcefield Therapeutics, and Heqet Therapeutics, and is a member of the Scientific Advisory Boards of Trizell Holding SA and DINAQR AG.

Author information

Ajay M Shah https://orcid.org/0000-0002-6547-0631

Mauro Giacca https://orcid.org/0000-0003-2927-7225

Article

Publisher ID: ehac463

DOI: 10.1093/eurheartj/ehac463

PMC ID: 9659475

PubMed ID: 36106499

SO-VID: 726c6ee7-0590-4a93-9aff-f7e4e25bb413

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 29 December 2021

Date revision received : 29 July 2022

Date accepted : 11 August 2022

Page count

Pages: 14

Funding

Funded by: British Heart Foundation, doi 10.13039/501100000274;

Award ID: CH/1999001/11735, RE/18/2/34213, RM/17/3/33381

Funded by: Fondation Leducq, doi 10.13039/501100001674;

Award ID: 17CVD04

Funded by: European Research Council, doi 10.13039/501100000781;

Award ID: 787971

Funded by: British Heart Foundation, doi 10.13039/501100000274;

Award ID: RG/19/11/34633

Funded by: European Commission Horizon;

Award ID: 825670

Award ID: 874764

Funded by: National Institute for Health Research Biomedical Research Centre at Guy’s;

Funded by: Thomas’ NHS Foundation Trust with King’s College London;

Award ID: IS-BRC-543 1215-20006

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Small non-coding RNA therapeutics for cardiovascular disease

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Karger: Cardiovascular System

Most cited references 200

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

MicroRNAs: genomics, biogenesis, mechanism, and function.

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