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      RNA‐based medicine: from molecular mechanisms to therapy

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          Abstract

          RNA‐based therapeutics have the potential to revolutionize the treatment and prevention of human diseases. While early research faced setbacks, it established the basis for breakthroughs in RNA‐based drug design that culminated in the extraordinarily fast development of mRNA vaccines to combat the COVID‐19 pandemic. We have now reached a pivotal moment where RNA medicines are poised to make a broad impact in the clinic. In this review, we present an overview of different RNA‐based strategies to generate novel therapeutics, including antisense and RNAi‐based mechanisms, mRNA‐based approaches, and CRISPR‐Cas‐mediated genome editing. Using three rare genetic diseases as examples, we highlight the opportunities, but also the challenges to wide‐ranging applications of this class of drugs.

          Abstract

          This review discusses the latest research on RNA‐based therapeutics, from design to the clinic.

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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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              A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.

              Martin Jinek, Krzysztof Chylinski, Ines Fonfara … (2012)
              Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide bacteria and archaea with adaptive immunity against viruses and plasmids by using CRISPR RNAs (crRNAs) to guide the silencing of invading nucleic acids. We show here that in a subset of these systems, the mature crRNA that is base-paired to trans-activating crRNA (tracrRNA) forms a two-RNA structure that directs the CRISPR-associated protein Cas9 to introduce double-stranded (ds) breaks in target DNA. At sites complementary to the crRNA-guide sequence, the Cas9 HNH nuclease domain cleaves the complementary strand, whereas the Cas9 RuvC-like domain cleaves the noncomplementary strand. The dual-tracrRNA:crRNA, when engineered as a single RNA chimera, also directs sequence-specific Cas9 dsDNA cleavage. Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.
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                Author and article information

                Contributors
                Jörg Vogel:
                ORCID: https://orcid.org/0000-0003-2220-1404
                joerg.vogel@uni-wuerzburg.de
                Journal
                Journal ID (nlm-ta): EMBO J
                Journal ID (iso-abbrev): EMBO J
                Journal ID (doi): 10.1002/(ISSN)1460-2075
                Journal ID (publisher-id): EMBJ
                Journal ID (hwp): embojnl
                Title: The EMBO Journal
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0261-4189
                ISSN (Electronic): 1460-2075
                Publication date (Electronic): 20 September 2023
                Publication date Collection: November 2023
                Publication date PMC-release: 20 September 2023
                Volume: 42
                Issue: 21 ( doiID: 10.1002/embj.v42.21 )
                Electronic Location Identifier: e114760
                Affiliations
                [ 1 ] Helmholtz Institute for RNA‐based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI) Würzburg Germany
                [ 2 ] Institute of Molecular Infection Biology (IMIB) University of Würzburg Würzburg Germany
                Author notes
                [*] [* ] Corresponding author. Tel: +49 931 31 82575; E‐mail: joerg.vogel@ 123456uni-wuerzburg.de

                Author information
                https://orcid.org/0000-0001-7695-2049
                https://orcid.org/0000-0003-2220-1404
                Article
                Publisher ID: EMBJ2023114760
                DOI: 10.15252/embj.2023114760
                PMC ID: 10620767
                PubMed ID: 37728251
                SO-VID: ddc483b8-c429-497a-ae21-9f3527678f6b
                Copyright © © 2023 The Authors. Published under the terms of the CC BY 4.0 license
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date revision received : 24 August 2023
                Date received : 14 June 2023
                Date accepted : 29 August 2023
                Page count
                Figures: 8, Tables: 1, Pages: 20, Words: 19787
                Funding
                Funded by: Elite Network Bavaria/Elitenetzwerk Bayern
                Categories
                Subject: Review
                Subject: Reviews
                Custom metadata
                source-schema-version-number 2.0
                cover-date 2 November 2023
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.4 mode:remove_FC converted:02.11.2023

                ScienceOpen disciplines: Molecular biology
                Keywords: antisense oligonucleotide drug,crispr‐cas therapy,mrna therapeutics,rare genetic disease,rna interference,genetics, gene therapy & genetic disease,pharmacology & drug discovery,rna biology
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: antisense oligonucleotide drug, crispr‐cas therapy, mrna therapeutics, rare genetic disease, rna interference, genetics, gene therapy & genetic disease, pharmacology & drug discovery, rna biology

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