Nucleoside-modified messenger RNA

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A nucleoside-modified messenger RNA (modRNA) is a synthetic messenger RNA (mRNA) in which some nucleosides are replaced by other naturally modified nucleosides or by synthetic nucleoside analogues. [1] modRNA is used to induce the production of a desired protein in certain cells. An important application is the development of mRNA vaccines, of which the first authorized were COVID-19 vaccines (such as Comirnaty and Spikevax).

Contents

Background

A ribosome (depicted in green) creates a protein (depicted here as a string of beads representing amino acids) encoded in an mRNA (depicted as a ribbon of nucleotides) that may be modified to reduce inflammation in the cell. Ribosome mRNA translation en.svg
A ribosome (depicted in green) creates a protein (depicted here as a string of beads representing amino acids) encoded in an mRNA (depicted as a ribbon of nucleotides) that may be modified to reduce inflammation in the cell.

mRNA is produced by synthesising a ribonucleic acid (RNA) strand from nucleotide building blocks according to a deoxyribonucleic acid (DNA) template, a process that is called transcription. [2] When the building blocks provided to the RNA polymerase include non-standard nucleosides such as pseudouridine — instead of the standard adenosine, cytidine, guanosine, and uridine nucleosides — the resulting mRNA is described as nucleoside-modified. [3]

Production of protein begins with assembly of ribosomes on the mRNA, the latter then serving as a blueprint for the synthesis of proteins by specifying their amino acid sequence based on the genetic code in the process of protein biosynthesis called translation. [4]

Overview

To induce cells to make proteins that they do not normally produce, it is possible to introduce heterologous mRNA into the cytoplasm of the cell, bypassing the need for transcription. In other words, a blueprint for foreign proteins is "smuggled" into the cells. To achieve this goal, however, one must bypass cellular systems that prevent the penetration and translation of foreign mRNA. There are nearly-ubiquitous enzymes called ribonucleases (also called RNAses) that break down unprotected mRNA. [5] There are also intracellular barriers against foreign mRNA, such as innate immune system receptors, toll-like receptor (TLR) 7 and TLR8, located in endosomal membranes. RNA sensors like TLR7 and TLR8 can dramatically reduce protein synthesis in the cell, trigger release of cytokines such as interferon and TNF-alpha, and when sufficiently intense lead to programmed cell death. [6]

The inflammatory nature of exogenous RNA can be masked by modifying the nucleosides in mRNA. [7] For example, uridine can be replaced with a similar nucleoside such as pseudouridine (Ψ) or N1-methyl-pseudouridine (m1Ψ), [8] and cytosine can be replaced by 5-methylcytosine. [9] Some of these, such as pseudouridine and 5-methylcytosine, occur naturally in eukaryotes, [10] while m1Ψ occurs naturally in archaea. [11] Inclusion of these modified nucleosides alters the secondary structure of the mRNA, which can reduce recognition by the innate immune system while still allowing effective translation. [9]

Significance of untranslated regions

A normal mRNA starts and ends with sections that do not code for amino acids of the actual protein. These sequences at the 5′ and 3′ ends of an mRNA strand are called untranslated regions (UTRs). The two UTRs at their strand ends are essential for the stability of an mRNA and also of a modRNA as well as for the efficiency of translation, i.e. for the amount of protein produced. By selecting suitable UTRs during the synthesis of a modRNA, the production of the target protein in the target cells can be optimised. [5] [12]

Delivery

Comparing uptake of RNA and modRNA by the cell Comparing uptake of RNA and modRNA by the cell.jpg
Comparing uptake of RNA and modRNA by the cell

Various difficulties are involved in the introduction of modRNA into certain target cells. First, the modRNA must be protected from ribonucleases. [5] This can be accomplished, for example, by wrapping it in liposomes. Such "packaging" can also help to ensure that the modRNA is absorbed into the target cells. This is useful, for example, when used in vaccines, as nanoparticles are taken up by dendritic cells and macrophages, both of which play an important role in activating the immune system. [13]

Furthermore, it may be desirable that the modRNA applied is introduced into specific body cells. This is the case, for example, if heart muscle cells are to be stimulated to multiply. In this case, the packaged modRNA can be injected directly into an artery such as a coronary artery. [14]

Applications

An important field of application are mRNA vaccines.

Replacing uridine with pseudouridine to evade the innate immune system was pioneered by Karikó and Weissman in 2005. [15] [16] They won the 2023 Nobel Prize in Physiology or Medicine as a result of their work. [17]

Another milestone was achieved by demonstrating the life-saving efficacy of nucleoside modified mRNA in a mouse model of a lethal lung disease by the team of Kormann and others in 2011. [18]

N1-methyl-pseudouridine was used in vaccine trials against Zika, [19] [20] [21] HIV-1, [21] influenza, [21] and Ebola [22] in 2017–2018. [23] : 5 

The first authorized for use in humans were COVID-19 vaccines to address SARS-CoV-2. [24] [25] [26] [27] [28] [29] [30] Examples of COVID-19 vaccines using modRNA include those developed by the cooperation of BioNTech/Pfizer (BNT162b2), and by Moderna (mRNA-1273). [31] [32] [33] The zorecimeran vaccine developed by Curevac, however, uses unmodified mRNA, [34] instead relying on codon optimization to minimize the presence of uridine. This vaccine is less effective, however. [35] [16]

Other possible uses of modRNA include the regeneration of damaged heart muscle tissue, [36] [37] an enzyme-replacement tool [38] and cancer therapy. [39] [40]

Related Research Articles

<span class="mw-page-title-main">RNA</span> Family of large biological molecules

Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself or by forming a template for the production of proteins. RNA and deoxyribonucleic acid (DNA) are nucleic acids. The nucleic acids constitute one of the four major macromolecules essential for all known forms of life. RNA is assembled as a chain of nucleotides. Cellular organisms use messenger RNA (mRNA) to convey genetic information that directs synthesis of specific proteins. Many viruses encode their genetic information using an RNA genome.

<i>Adenoviridae</i> Family of viruses

Adenoviruses are medium-sized, nonenveloped viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from their initial isolation from human adenoids in 1953.

Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: "transformation" is typically used to describe non-viral DNA transfer in bacteria and non-animal eukaryotic cells, including plant cells. In animal cells, transfection is the preferred term as transformation is also used to refer to progression to a cancerous state (carcinogenesis) in these cells. Transduction is often used to describe virus-mediated gene transfer into eukaryotic cells.

<span class="mw-page-title-main">RNA editing</span> Molecular process

RNA editing is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. It occurs in all living organisms and is one of the most evolutionarily conserved properties of RNAs. RNA editing may include the insertion, deletion, and base substitution of nucleotides within the RNA molecule. RNA editing is relatively rare, with common forms of RNA processing not usually considered as editing. It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.

<span class="mw-page-title-main">Pseudouridine</span> Chemical compound

Pseudouridine is an isomer of the nucleoside uridine in which the uracil is attached via a carbon-carbon instead of a nitrogen-carbon glycosidic bond.

In molecular biology, small nucleolar RNAs (snoRNAs) are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs. There are two main classes of snoRNA, the C/D box snoRNAs, which are associated with methylation, and the H/ACA box snoRNAs, which are associated with pseudouridylation. SnoRNAs are commonly referred to as guide RNAs but should not be confused with the guide RNAs that direct RNA editing in trypanosomes or the guide RNAs (gRNAs) used by Cas9 for CRISPR gene editing.

<span class="mw-page-title-main">Small nucleolar RNA SNORA44</span> Non-coding RNA molecule which functions in the biogenesis of other small nuclear RNAs

In molecular biology, Small nucleolar RNA SNORA44 is a non-coding RNA (ncRNA) molecule which functions in the biogenesis (modification) of other small nuclear RNAs (snRNAs). This type of modifying RNA is located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis. It is known as a small nucleolar RNA (snoRNA) and also often referred to as a 'guide RNA'.

<span class="mw-page-title-main">CTP synthase 1</span> Protein-coding gene in the species Homo sapiens

CTP synthase 1 is an enzyme that is encoded by the CTPS1 gene in humans. CTP synthase 1 is an enzyme in the de novo pyrimidine synthesis pathway that catalyses the conversion of uridine triphosphate (UTP) to cytidine triphosphate (CTP). CTP is a key building block for the production of DNA, RNA and some phospholipids.

Peptide-based synthetic vaccines are subunit vaccines made from peptides. The peptides mimic the epitopes of the antigen that triggers direct or potent immune responses. Peptide vaccines can not only induce protection against infectious pathogens and non-infectious diseases but also be utilized as therapeutic cancer vaccines, where peptides from tumor-associated antigens are used to induce an effective anti-tumor T-cell response.

Within the field of molecular biology, the epitranscriptome includes all the biochemical modifications of the RNA within a cell. In analogy to epigenetics that describes "functionally relevant changes to the genome that do not involve a change in the nucleotide sequence", epitranscriptomics involves all functionally relevant changes to the transcriptome that do not involve a change in the ribonucleotide sequence. Thus, the epitranscriptome can be defined as the ensemble of such functionally relevant changes.

Neoepitopes are a class of major histocompatibility complex (MHC) bounded peptides. They represent the antigenic determinants of neoantigens. Neoepitopes are recognized by the immune system as targets for T cells and can elicit immune response to cancer.

mRNA vaccine Type of vaccine

An mRNAvaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen-encoding mRNA into cells, which use the designed mRNA as a blueprint to build foreign protein that would normally be produced by a pathogen or by a cancer cell. These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect the RNA strands and help their absorption into the cells.

<span class="mw-page-title-main">COVID-19 vaccine</span> Vaccine against SARS-CoV-2

A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID‑19).

<span class="mw-page-title-main">Katalin Karikó</span> Hungarian-American biochemist (born 1955)

Katalin "Kati" Karikó is a Hungarian-American biochemist who specializes in ribonucleic acid (RNA)-mediated mechanisms, particularly in vitro-transcribed messenger RNA (mRNA) for protein replacement therapy. Karikó laid the scientific groundwork for mRNA vaccines, overcoming major obstacles and skepticism in the scientific community. Karikó received the Nobel Prize in Physiology or Medicine in 2023 for her work, along with American immunologist Drew Weissman.

<span class="mw-page-title-main">CureVac COVID-19 vaccine</span> Vaccine candidate against COVID-19

The CureVac COVID-19 vaccine was a COVID-19 vaccine candidate developed by CureVac N.V. and the Coalition for Epidemic Preparedness Innovations (CEPI). The vaccine showed inadequate results in its Phase III trials with only 47% efficacy. In October 2021 CureVac abandoned further development and production plans for CVnCoV and refocused efforts on a cooperation with GlaxoSmithKline.

<span class="mw-page-title-main">Viral vector vaccine</span> Type of vaccine

A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material (DNA) that can be transcribed by the recipient's host cells as mRNA coding for a desired protein, or antigen, to elicit an immune response. As of April 2021, six viral vector vaccines, four COVID-19 vaccines and two Ebola vaccines, have been authorized for use in humans.

<span class="mw-page-title-main">Walvax COVID-19 vaccine</span> Vaccine candidate against COVID-19

AWcorna, originally termed ARCoV and also known as the Walvax COVID-19 vaccine, is an mRNA COVID-19 vaccine developed by Walvax Biotechnology, Suzhou Abogen Biosciences, and the PLA Academy of Military Science. In contrast to other mRNA COVID-19 vaccines, such as those by Pfizer-BioNTech and Moderna, this vaccine primarily targets the SARS-CoV-2 receptor-binding domain of the spike protein, rather than the entire spike protein. It is approved for Phase III trials in China, Mexico, Indonesia, and Nepal.

<span class="mw-page-title-main">N1-Methylpseudouridine</span> Chemical compound

N1-Methylpseudouridine is a natural archaeal tRNA component, and "hypermodified" pyrimidine nucleoside used in biochemistry and molecular biology for in vitro transcription and is found in the SARS-CoV-2 mRNA vaccines tozinameran (Pfizer–BioNTech) and elasomeran (Moderna).

<span class="mw-page-title-main">Riccardo Cortese</span> Italian scientist and entrepreneur

Riccardo Cortese was an Italian scientist, entrepreneur, and innovator in the field of gene expression, drug discovery and genetic vaccines. His work led to the development of novel therapeutic strategies for the prevention and cure of viral infections, including HIV, HCV, Ebola and RSV. He pioneered a novel platform technology based on simian adenoviral vectors for prophylactic and therapeutic vaccines, and authored more than 300 publications in peer-reviewed journals in the field of gene expression, transcriptional control, molecular virology and immunology.

Self-amplifying RNA (saRNA), also termed self-replicating RNA (srRNA), is a type of mRNA molecule engineered to replicate itself within host cells, enhancing protein expression and boosting the immune response, making it a promising tool for vaccines and other therapeutic applications. As a "next-generation" mRNA, saRNA is designed to achieve greater protein expression with a reduced dose compared to conventional mRNA. Unlike conventional mRNA, which has a short half-life and limited ability to express proteins for an extended time, saRNA can sustain protein expression for longer periods. saRNA are based on positive single stranded RNA viruses most commonly alphaviruses such as Venezuelan equine encephalitis virus.

References

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