The Pivotal Role of Chemical Modifications in mRNA Therapeutics

Abstract

After over a decade of development, mRNA has recently matured into a potent modality for therapeutics. The advantages of mRNA therapeutics, including their rapid development and scalability, have been highlighted due to the SARS-CoV-2 pandemic, in which the first two clinically approved mRNA vaccines have been spotlighted. These vaccines, as well as multiple other mRNA therapeutic candidates, are modified to modulate their immunogenicity, stability, and translational efficiency. Despite the importance of mRNA modifications for harnessing the full efficacy of mRNA drugs, the full breadth of potential modifications has yet to be explored clinically. In this review, we survey the field of mRNA modifications, highlighting their ability to tune the properties of mRNAs. These include cap and tail modifications, nucleoside substitutions, and chimeric mRNAs, each of which represents a component of mRNA that can be exploited for modification. Additionally, we cover clinical and preclinical trials of the modified mRNA platform not only to illustrate the promise of modified mRNAs but also to call attention to the room for diversifying future therapeutics.

DLin-MC3-Containing mRNA Lipid Nanoparticles Induce an Antibody Th2-Biased Immune Response Polarization in a Delivery Route-Dependent Manner in Mice

“…After the COVID-19 mass vaccination campaign, several studies highlighted that mRNA-based vaccines were not able to induce long-term immunity [ 19 , 20 ]. The main approaches to improve in vivo efficacy are based on the selection and optimization of the RNA sequence [ 21 ] and the delivery system used [ 22 ]. Other improvements have been proposed such as heterologous vaccine regimens (consisting of an immunization scheme combining different types of vaccines [ 23 ]) or the change in administration route.…”

The Storage and In-Use Stability of mRNA Vaccines and Therapeutics: Not A Cold Case

“…Interestingly, the same situation is described in a recently published overview on the effects of chemical modifications of mRNA molecules. It only considers in cell/in vivo performance as leading outcome parameter, and effects of these modifications on pharmaceutical properties of mRNA, such as storage stability or shelf life, have not been determined 37 .…”

Towards the controlled enzymatic synthesis of LNA containing oligonucleotides

“…For instance, antisense oligonucleotides consist of short, fully-modified sequences and the de novo genome synthesis requires the error-free assembly of massive amounts of shorter stretches of unmodified DNA ( Masaki et al, 2022 ; Matthey-Doret et al, 2022 ). On the other end of the spectrum, mRNA vaccines require the production of long (several thousands of nucleotides) oligonucleotides containing modified residues such as N 1-methyl-pseudouridine ( Nance and Meier, 2021 ; Dousis et al, 2022 ) while studies aiming at understanding the mechanisms and functions of larger RNAs such as long non-coding RNAs or mRNA call in for the synthesis of long, heavily modified sequences ( Zuckerman et al, 2020 ; Statello et al, 2021 ; Liu and Wang, 2022 ).…”