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Tytuł pozycji:

Impact of mRNA chemistry and manufacturing process on innate immune activation.

Tytuł :
Impact of mRNA chemistry and manufacturing process on innate immune activation.
Autorzy :
Nelson J; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Sorensen EW; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Mintri S; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Rabideau AE; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Zheng W; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Besin G; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Khatwani N; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Su SV; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Miracco EJ; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Issa WJ; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Hoge S; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Stanton MG; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Joyal JL; Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
Pokaż więcej
Źródło :
Science advances [Sci Adv] 2020 Jun 24; Vol. 6 (26), pp. eaaz6893. Date of Electronic Publication: 2020 Jun 24 (Print Publication: 2020).
Typ publikacji :
Journal Article
Język :
English
Imprint Name(s) :
Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-
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Entry Date(s) :
Date Created: 20200709 Latest Revision: 20200709
Update Code :
20210914
PubMed Central ID :
PMC7314518
DOI :
10.1126/sciadv.aaz6893
PMID :
32637598
Czasopismo naukowe
Messenger RNA (mRNA) represents an attractive therapeutic modality for potentially a wide range of clinical indications but requires uridine chemistry modification and/or tuning of the production process to prevent activation of cellular innate immune sensors and a concomitant reduction in protein expression. To decipher the relative contributions of these factors on immune activation, here, we compared, in multiple cell and in vivo models, mRNA that encodes human erythropoietin incorporating either canonical uridine or N 1-methyl-pseudouridine (1mΨ), synthesized by either a standard process shown to have double-stranded RNA (dsRNA) impurities or a modified process that yields a highly purified mRNA preparation. Our data demonstrate that the lowest stimulation of immune endpoints was with 1mΨ made by the modified process, while mRNA containing canonical uridine was immunostimulatory regardless of process. These findings confirm that uridine modification and the reduction of dsRNA impurities are both necessary and sufficient at controlling the immune-activating profile of therapeutic mRNA.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

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