Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo

Kauffman, Kevin J and Mir, Faryal F and Jhunjhunwala, Siddharth and Kaczmarek, James C and Hurtado, Juan E and Yang, Jung H and Webber, Matthew J and Kowalski, Piotr S and Heartlein, Michael W and DeRosa, Frank and Anderson, Daniel G (2016) Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo. In: BIOMATERIALS, 109 . pp. 78-87.

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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 netitrophilia, myeloid cell activation, and up-regulation of four serum cytoldnes. 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. (C) 2016 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Publication:	BIOMATERIALS
Additional Information:	Copy right for this article belongs to the ELSEVIER SCI LTD, THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
Department/Centre:	Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited:	03 Dec 2016 10:03
Last Modified:	26 Oct 2018 14:44
URI:	http://eprints.iisc.ac.in/id/eprint/55392

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