MRNA-based therapies and their clinical prospects

Abstract

<p indent="0mm">The striking effectiveness of messenger ribonucleic acid (mRNA) vaccines against coronavirus disease 2019 (COVID-19) not only offers hope to end the current pandemic, but also presents mRNA-based therapeutics as a potential new treatment class that may help in the fight against other diseases. <italic>In vitro</italic>-transcribed (IVT) mRNA is engineered to structurally resemble naturally occurring mature and processed eukaryotic mRNA. Such synthetic mRNAs deliver genetic information that allows the translational machinery of the host cells to produce many copies of the encoded proteins, which can function as antigens to boost immune responses or as supplementary beneficial proteins, resulting in a therapeutic effect. With recent developments in mRNA <italic>in vivo</italic> delivery platforms and the improvement of modified regulatory systems, the stability and transfection efficiency of mRNA have been greatly improved. Modified regulatory systems utilize caps, 5′ and 3′ untranslated regions, open reading frames, Poly(A) tails, and chemically modified nucleotides. Notably, <italic>in vivo</italic> delivery platforms can either be a non-targeted or targeted delivery system. Currently, mRNA-based therapeutics, including vaccines and protein replacement therapy, are being clinically developed for cancers, infectious diseases, and rare diseases. Common mRNA cancer vaccines include dendritic cell mRNA cancer vaccine, naked mRNA injection, mRNA encoding CAR, and other combination therapies. There are two main types of mRNA vaccines against infectious diseases: Non-replicating and self-amplifying. In addition, mRNA protein replacement therapies are available; these are therapies in which body cells are transfected with mRNA, and the translated proteins are used to supplement the lack of proteins in the body or replace abnormal proteins that hinder normal cellular pathways. mRNA therapies are also used in treatment of rare genetic diseases, such as Fabry disease, methylmalonic acidemia, ornithine carbamoyltransferase deficiency, and acute intermittent porphyria. Furthermore, IVT mRNA encoding genome-editing nucleases has been used as a novel method to perform gene editing. mRNA therapies have the advantages of fast preparation, low production costs, and safety. However, there are still challenges to be overcome for the successful clinical application of mRNA-based therapies. For example, mRNA stability and target specificity still require improvement. In terms of stability, quality control needs to be improved and the negative impact of immunogenicity should be reduced. Quality control refers to improving the ability to detect residual template deoxyribonucleic acid, IVT reaction by-products, and incomplete mRNA. In addition, when comparing independent routes of administration, the variation between- and within individuals, particularly due to the mRNA dosage and protein effects has not been thoroughly studied. To understand the up-to-date development and research status of mRNA therapies, this review focuses on molecular design, delivery system, and clinical research status of mRNA therapies.