Recombinant messenger RNA technology and its application in cancer immunotherapy, transcript replacement therapies, pluripotent stem cell induction, and beyond

Abstract

In recent years, the interest in using messenger RNA (mRNA) as a therapeutic means to tackle different diseases has enormously increased. This holds true not only for numerous preclinical studies, but mRNA has also entered the clinic to fight cancer. The advantages of using mRNA compared to DNA were recognized very early on, e.g., the lack of risk for genomic integration, or the expression of the encoded protein in the cytoplasm without the need to cross the nuclear membrane. However, it was generally assumed that mRNA is just not stable enough to give rise to sufficient expression of the encoded protein. Yet, an initially small group of mRNA aficionados could demonstrate that the stability of mRNA and the efficiency, by which the encoded protein is translated, can be significantly increased by selecting the right set of cis-acting structural elements (including the 5'-cap, 5'- and 3'-untranslated regions, poly(A)-tail, and modified building blocks). In parallel, significant advances in RNA packaging and delivery have been made, extending the potential for this molecule. This paved the way for further work to prove mRNA as a promising therapeutic for multiple diseases. Here, we review the developments to optimize mRNA regarding stability, translational efficiency, and immune-modulating properties to enhance its functionality and efficacy as a therapeutic. Furthermore, we summarize the current status of preclinical and clinical studies that use mRNA for cancer immunotherapy, for the expression of functional proteins as so-called transcript (or protein) replacement therapy, as well as for induction of pluripotent stem cells.

Human cellular CYBA UTR sequences increase mRNA translation without affecting the half-life of recombinant RNA transcripts

“…Furthermore, Holtkamp et al ., have shown that 2 copies of 3′ UTR from β-globin result in increased protein levels and mRNA stability only in immature dendritic cells, whereas in mature dendritic cells, no effect could be observed18. Cell specificity of UTRs when combined with mRNA has been also observed for other cells and tissues and has been discussed in the recent reviews4142.…”

Overexpression of mRNA‑decapping enzyme 1a affects survival rate in colorectal carcinoma

“…Thus, the identification of novel diagnosis and treatment methods is required. The roles of mRNAs in eukaryotic cells have been well characterized; they are important in regulating gene expression and may be promising in cancer therapies (22,23). Notably, eukaryotic cellular mRNAs possess distinctive sections at their 5'-and 3'-ends.…”

Translation of Angiotensin-Converting Enzyme 2 upon Liver- and Lung-Targeted Delivery of Optimized Chemically Modified mRNA

“…Cell type and cell state have a strong impact on how the cell reacts to variations in artificially introduced mRNA sequences. 42,[50][51][52] The biological implications of these modifications need to be carefully evaluated. UTRs are key elements in the mRNA sequence for translation initiation, elongation, and termination as well as intracellular localization and mRNA stability, 53,54 all of which have a significant impact on final protein expression kinetics.…”