Position-specific nucleoside-ribose modifications may improve uncapped mRNA stability and translation.
Evidence
Chemistry-based synthetic mRNA platform experiments tested site-specific ORF, 5´-UTR, and poly(A) tail modifications and found that 2´-F at the first nucleoside of codons increased stability without compromising translation.
Caveat
The abstract reports a design framework and expression improvements for synthetic uncapped mRNA, not clinical therapeutic efficacy or safety.
Simplified
Despite the remarkable success of mRNA vaccines, improving the translational efficiency of remains a critical challenge to their widespread clinical application. Here we systematically evaluate chemical modifications to improve the translational activity and stability of uncapped mRNA. We employ a primarily chemistry-based synthetic approach, which is crucial for the position-specific introduction of chemical modifications, enabling detailed structure-activity relationship studies, hitherto unattainable with conventional methods. A pivotal innovation herein is the introduction of 2´-F modification at the first nucleoside of the codon in the open reading frame, which significantly bolsters the stability of mRNA without compromising its translation. Additional modifications at the 5´-UTR and poly(A) tail with other types of nucleoside and phosphate analogs also exemplify the importance of terminal modifications for improved translation. Precise control of these modification patterns achieves higher peptide expression than conventional in vitro-transcribed mRNA. These findings offer a unique framework for designing effective mRNA-based therapeutics.
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Competing interests: Competing Interest Statement: H.A. is a cofounder of Crafton Biotechnology. The company focuses on the development of mRNA therapeutics. H.I., M.H., K.M., T.A., K.A., K.K., H.Y., A.H., K.H., S.S., and J.Y. are employees of Kyowa Kirin Co. Ltd. International patents application covering part of this work has been filed by Nagoya University and Kyowa Kirin Co., Ltd. The remaining authors declare no competing interests.
