N(1)-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice

Journal of Controlled Release : Official Journal of the Controlled Release Society
Oliwia AndriesTasuku Kitada

Abstract

Messenger RNA as a therapeutic modality is becoming increasingly popular in the field of gene therapy. The realization that nucleobase modifications can greatly enhance the properties of mRNA by reducing the immunogenicity and increasing the stability of the RNA molecule (the Kariko paradigm) has been pivotal for this revolution. Here we find that mRNAs containing the N(1)-methylpseudouridine (m1Ψ) modification alone and/or in combination with 5-methylcytidine (m5C) outperformed the current state-of-the-art pseudouridine (Ψ) and/or m5C/Ψ-modified mRNA platform by providing up to ~44-fold (when comparing double modified mRNAs) or ~13-fold (when comparing single modified mRNAs) higher reporter gene expression upon transfection into cell lines or mice, respectively. We show that (m5C/)m1Ψ-modified mRNA resulted in reduced intracellular innate immunogenicity and improved cellular viability compared to (m5C/)Ψ-modified mRNA upon in vitro transfection. The enhanced capability of (m5C/)m1Ψ-modified mRNA to express proteins may at least partially be due to the increased ability of the mRNA to evade activation of endosomal Toll-like receptor 3 (TLR3) and downstream innate immune signaling. We believe that the (m5C/)m1Ψ-mRNA platform pre...Continue Reading

References

Mar 23, 1990·Science·J A WolffP L Felgner
Sep 18, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Katalin KarikóDrew Weissman
May 12, 2010·Nucleic Acids Research·Bart R AndersonKatalin Karikó
Nov 13, 2010·Nucleic Acids Research·William A CantaraPaul F Agris
Jan 11, 2011·Nature Biotechnology·Michael S D KormannCarsten Rudolph
Nov 3, 2012·Nucleic Acids Research·Magdalena A MachnickaHenri Grosjean
Feb 9, 2013·The Journal of Clinical Investigation·Lauren E MaysMichael S D Kormann
Feb 9, 2013·Trends in Biochemical Sciences·Junhui Ge, Yi-Tao Yu
Feb 14, 2013·Journal of Controlled Release : Official Journal of the Controlled Release Society·Oliwia AndriesNiek N Sanders
Jan 9, 2015·Expert Review of Vaccines·Oliwia AndriesRon Weiss
Jan 21, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Miyuki BabaKazunori Kataoka
Mar 25, 2015·Nature·Robert C SpitaleHoward Y Chang
Mar 25, 2015·Nature·Claudio R AlarcónSohail F Tavazoie
May 20, 2015·Nature Biotechnology·Azita J MahinyMichael S D Kormann
Aug 4, 2015·Nature Biotechnology·Liliana WroblewskaRon Weiss
Aug 13, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Norbert PardiDrew Weissman

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Citations

Oct 31, 2015·Pharmaceutical Research·Katrien RemautDaisy Vanrompay
Feb 26, 2016·Bioconjugate Chemistry·Bin LiYizhou Dong
Nov 22, 2015·Molecular and Cellular Pediatrics·Justin S AntonyMichael S D Kormann
May 10, 2016·Nucleosides, Nucleotides & Nucleic Acids·Muthian ShanmugasundaramAnilkumar R Kore
Apr 9, 2017·Molecular Therapy : the Journal of the American Society of Gene Therapy·Nishat SultanaLior Zangi
Jan 13, 2018·Nature Reviews. Drug Discovery·Norbert PardiDrew Weissman
Aug 9, 2018·Nucleic Acid Therapeutics·Ruchi JainTirtha Chakraborty
Sep 8, 2018·Nature Reviews. Drug Discovery·Fernando PastorIgnacio Melero
Jan 22, 2019·Journal of Biomedical Materials Research. Part a·Satoshi Uchida, Kazunori Kataoka
May 20, 2018·Scientific Reports·Susan Liu-ChenZhaozhong Han
Feb 26, 2020·Nanomaterials·Itziar Gómez-AguadoAna Del Pozo-Rodríguez
Jun 4, 2020·Vaccines·Aryamav PattnaikAsit K Pattnaik
Jul 8, 2020·International Journal of Molecular Sciences·Julia MathlinTeresa Colombo
Nov 1, 2016·Current Protocols in Stem Cell Biology·Yuhui NiJiwu Wang
May 10, 2018·The Journal of Experimental Medicine·Norbert PardiDrew Weissman
Dec 22, 2017·NPJ Vaccines·Johannes LutzMariola Fotin-Mleczek
Apr 5, 2018·Vaccines·Francesco Berlanda Scorza, Norbert Pardi
Feb 24, 2019·Journal of Translational Medicine·Lien Van Hoecke, Kenny Roose
Apr 23, 2019·Nano Research·Qingqing XiongJinjun Shi
Oct 20, 2018·Cellular and Molecular Life Sciences : CMLS·Thomas SchlakeIngo Jordan
Apr 18, 2020·Wiley Interdisciplinary Reviews. RNA·Phillip J McCownJessica A Brown
Jun 29, 2017·Genome Medicine·James C KaczmarekDaniel G Anderson
Nov 15, 2018·Scientific Reports·A K M Ashiqul HaqueMichael S D Kormann
Feb 1, 2019·Genes·Isabel FreundAlexander H Dalpke
Dec 14, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yitian XuDavid G Russell
Oct 18, 2018·Nature Chemical Biology·Tyler E WagnerRon Weiss
Feb 25, 2020·Nucleic Acids Research·Callum J C ParrHirohide Saito
Feb 13, 2020·NPJ Vaccines·Nicholas A C JacksonFrank DeRosa
May 14, 2020·Advanced Biosystems·Hirohisa OhnoHirohide Saito
Aug 26, 2017·Nature Biomedical Engineering·Bin LiYizhou Dong
Apr 12, 2019·Frontiers in Immunology·Cuiling ZhangJunwei Li
Apr 17, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Shota KurimotoSatoshi Uchida
Dec 3, 2016·Current Protocols in Nucleic Acid Chemistry·Muthian ShanmugasundaramAnilkumar R Kore
Jul 1, 2020·Advanced Drug Delivery Reviews·Darrell J IrvineMurillo Silva

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