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

Advanced Review

Britta Vallazza, Sebastian Petri, Marco A. Poleganov, Florian Eberle, Andreas N. Kuhn, Ugur Sahin

Published Online: Jun 09 2015

DOI: 10.1002/wrna.1288

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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. WIREs RNA 2015, 6:471–499. doi: 10.1002/wrna.1288 This article is categorized under: Translation > Translation Regulation RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA in Disease and Development > RNA in Disease

(a) Overview of structural messenger RNA (mRNA) features. (b) Examples of cap analogs used for in vitro transcription. m⁷GpppG results in the natural cap upon in vitro transcription, while antireverse cap analog (ARCA) and β‐S‐ARCA are modified to enhance capping and translation efficiency (see main text for references). Modifications are colored in red. The phosphorothioate cap analog β‐S‐ARCA exists in two diastereomers because of the presence of a stereogenic P center (labeled with *).

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