The pivotal role of uridine modifications in the development of mRNA technology

Authors

DOI:

https://doi.org/10.20883/medical.e938

Keywords:

mRNA vaccines, infectious diseases, cancer treatment, pseudouridine, Nobel Prize

Abstract

In 2023, Katalin Karikó and Drew Weissman were awarded the Nobel Prize in Physiology or Medicine for their nucleoside base modifications research that later enabled mRNA vaccine development against COVID‑19. This paper briefly reviews these achievements in the context of the development of mRNA technology and its enormous potential for medicine in the prevention of various infectious diseases and cancer treatment, including personalised therapies. It is beyond any doubt that discoveries made by Karikó and Weissman were pivotal in overcoming one of the major hurdles in the practical application of mRNA molecules, i.e., the recognition of exogenous mRNAs by endosomal Toll-like receptors and downstream innate immune response, ultimately leading to the decreased translational activity of delivered mRNA and its degradation. Although the Nobel Prize for Karikó and Weissman is fully justified, it must be stressed that mRNA technology would never unfold its potential for public health without a collective scientific effort encompassing over 40 years of research.

Downloads

Download data is not yet available.

References

The Nobel Prize in Physiology or Medicine 2023 [Internet]. Nobelprize.org. [cited 2023 Oct 5]. Available from: https://www.nobelprize.org/prizes/medicine/2023/press-release/

Stacey DW, Allfrey VG. Microinjection studies of duck globin messenger RNA translation in human and avian cells. Cell. 1976;9:725–732. DOI: https://doi.org/10.1016/0092-8674(76)90136-7

Dimitriadis GJ. Translation of rabbit globin mRNA introduced by liposomes into mouse lymphocytes. Nature. 1978;274:923–924. DOI: https://doi.org/10.1038/274923a0

Malone RW, Felgner PL, Verma IM. Cationic liposome-mediated RNA transfection. Proc Natl Acad Sci U S A. 1989;86:6077–6081. DOI: https://doi.org/10.1073/pnas.86.16.6077

Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990;247:1465–1468. DOI: https://doi.org/10.1126/science.1690918

Martinon F, Krishnan S, Lenzen G, Magné R, Gomard E, Guillet JG, et al. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur J Immunol. 1993;23:1719–1722. DOI: https://doi.org/10.1002/eji.1830230749

Conry RM, LoBuglio AF, Wright M, Sumerel L, Pike MJ, Johanning F, et al. Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Res. 1995;55:1397–1400.

Heiser A, Coleman D, Dannull J, Yancey D, Maurice MA, Lallas CD, et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest. 2002;109:409–417. DOI: https://doi.org/10.1172/JCI0214364

Liu A, Wang X. The pivotal role of chemical modifications in mRNA therapeutics. Front Cell Dev Biol . 2022;10: 901510. DOI: https://doi.org/10.3389/fcell.2022.901510

Karikó K, Buckstein M, Ni H, Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005;23:165–175. DOI: https://doi.org/10.1016/j.immuni.2005.06.008

Karikó K, Muramatsu H, Welsh FA, Ludwig J, Kato H, Akira S, et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. 2008;16:1833–1840. DOI: https://doi.org/10.1038/mt.2008.200

Anderson BR, Muramatsu H, Nallagatla SR, Bevilacqua PC, Sansing LH, Weissman D, et al. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res. 2010;38:5884–5892. DOI: https://doi.org/10.1093/nar/gkq347

Svitkin YV, Cheng YM, Chakraborty T, Presnyak V, John M, Sonenberg N. N1-methyl-pseudouridine in mRNA enhances translation through eIF2α-dependent and independent mechanisms by increasing ribosome density. Nucleic Acids Res. 2017;45:6023–6036. DOI: https://doi.org/10.1093/nar/gkx135

Andries O, Mc Cafferty S, De Smedt SC, Weiss R, Sanders NN, Kitada T. N1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. J Control Release. 2015;217:337–344. DOI: https://doi.org/10.1016/j.jconrel.2015.08.051

Nance KD, Meier JL. Modifications in an emergency: The role of N1-methylpseudouridine in COVID-19 vaccines. ACS Cent Sci. 2021;7:748–756. DOI: https://doi.org/10.1021/acscentsci.1c00197

Watson OJ, Barnsley G, Toor J, Hogan AB, Winskill P, Ghani AC. Global impact of the first year of COVID-19 vaccination: a mathematical modelling study. Lancet Infect Dis. 2022;22:1293–1302. DOI: https://doi.org/10.1016/S1473-3099(22)00320-6

Rzymski P, Szuster-Ciesielska A, Dzieciątkowski T, Gwenzi W, Fal A. mRNA vaccines: The future of prevention of viral infections? J Med Virol. 2023;95: e28572 DOI: https://doi.org/10.1002/jmv.28572

Rzymski P, Camargo CA, Fal A, Flisiak R, Gwenzi W, Kelishadi R, et al. COVID-19 Vaccine Boosters: The Good, the Bad, and the Ugly. Vaccines. 2021;9:1299. DOI: https://doi.org/10.3390/vaccines9111299

Rzymski P, Szuster-Ciesielska A. The COVID-19 vaccination still matters: Omicron variant is a final wake-up call for the rich to help the poor. Vaccines. 2022;10:1070. DOI: https://doi.org/10.3390/vaccines10071070

Pietrzak Ł, Polok K, Halik R, Szuster-Ciesielska A, Szczeklik W. Effectiveness of BNT162b2 vaccination in preventing COVID-19–associated death in Poland. Pol Arch Med Wewn. 2023;133:1-8. DOI: https://doi.org/10.20452/pamw.16575

Lorentzen CL, Haanen JB, Met Ö, Svane IM. Clinical advances and ongoing trials of mRNA vaccines for cancer treatment. Lancet Oncol. 2022;23:450–458. DOI: https://doi.org/10.1016/S1470-2045(22)00372-2

Xie N, Shen G, Gao W, Huang Z, Huang C, Fu L. Neoantigens: promising targets for cancer therapy. Signal Transduct Target Ther. 2023;8:9. DOI: https://doi.org/10.1038/s41392-022-01270-x

Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023;618:144–150. DOI: https://doi.org/10.1038/s41586-023-06063-y

Hald Albertsen C, Kulkarni JA, Witzigmann D, Lind M, Petersson K, Simonsen JB. The role of lipid components in lipid nanoparticles for vaccines and gene therapy. Adv Drug Deliv Rev. 2022;188:114416. DOI: https://doi.org/10.1016/j.addr.2022.114416

Grudzien-Nogalska E, Jemielity J, Kowalska J, Darzynkiewicz E, Rhoads RE. Phosphorothioate cap analogs stabilize mRNA and increase translational efficiency in mammalian cells. RNA. 2007 Oct;13(10):1745–55. DOI: https://doi.org/10.1261/rna.701307

Sikorski PJ, Warminski M, Kubacka D, Ratajczak T, Nowis D, Kowalska J, et al. The identity and methylation status of the first transcribed nucleotide in eukaryotic mRNA 5’ cap modulates protein expression in living cells. Nucleic Acids Res. 2020 Feb 28;48(4):1607–26. DOI: https://doi.org/10.1093/nar/gkaa032

Orlandini von Niessen AG, Poleganov MA, Rechner C, Plaschke A, Kranz LM, Fesser S, et al. Improving mRNA-based therapeutic gene delivery by expression-augmenting 3’ UTRs identified by cellular library screening. Mol Ther. 2019 Apr 10;27(4):824–36. DOI: https://doi.org/10.1016/j.ymthe.2018.12.011

Graham F. Daily briefing: ‘Elitist but essential’ — what our readers think about the Nobel Prizes. Nature [Internet]. 2023 Sep 29 [cited 2023 Oct 5]; Available from: https://www.nature.com/articles/d41586-023-03110-6 DOI: https://doi.org/10.1038/d41586-023-03110-6

Downloads

Published

2023-12-07

How to Cite

1.
Rzymski P. The pivotal role of uridine modifications in the development of mRNA technology. JMS [Internet]. 2023 Dec. 7 [cited 2024 Jun. 16];93(1):e938. Available from: https://jms.ump.edu.pl/index.php/JMS/article/view/938

Issue

Section

Thousand words about...
Received 2023-10-05
Accepted 2023-11-05
Published 2023-12-07