Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo
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Anderson_Efficacy and Immunogenicity.pdf
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Author(s)
Heartlein, Michael W.
DeRosa, Frank
Kauffman, Kevin John
Mir, Faryal
Jhunjhunwala, Siddharth
Kaczmarek, James Cliff
Hurtado, Juan E.
Yang, Jung H
Webber, Matthew
Kowalski, Piotr S
Date Issued
September 2016
Journal
Biomaterials
Publisher
Elsevier BV
Citation
Kauffman, Kevin J. et al. “Efficacy and Immunogenicity of Unmodified and Pseudouridine-Modified mRNA Delivered Systemically with Lipid Nanoparticles in Vivo.” Biomaterials 109 (December 2016): 78–87.
Version
Author's final manuscript
Abstract
mRNA has broad potential for treating diseases requiring protein expression. However, mRNA can also induce an immune response with associated toxicity. Replacement of uridine bases with pseudouridine has been postulated to modulate both mRNA immunogenicity and potency. Here, we explore the immune response and activity of lipid nanoparticle-formulated unmodified and pseudouridine-modified mRNAs administered systemically in vivo. Pseudouridine modification to mRNA had no significant effect on lipid nanoparticle physical properties, protein expression in vivo, or mRNA immunogenicity compared to unmodified mRNA when delivered systemically with liver-targeting lipid nanoparticles, but reduced in vitro transfection levels. Indicators of a transient, extracellular innate immune response to mRNA were observed, including neutrophilia, myeloid cell activation, and up-regulation of four serum cytokines. This study provides insight into the immune responses to mRNA lipid nanoparticles, and suggests that pseudouridine modifications may be unnecessary for therapeutic application of mRNA in the liver. Keywords: mRNA, Base modification, Pseudouridine, Lipid nanoparticle, In vivo, Immmune response
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.BIOMATERIALS.2016.09.006
