Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo
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 re...
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Elsevier BV
2018
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| Online Access: | http://hdl.handle.net/1721.1/119489 https://orcid.org/0000-0002-9436-2453 https://orcid.org/0000-0001-8046-2288 https://orcid.org/0000-0002-6516-7499 https://orcid.org/0000-0003-0624-3532 https://orcid.org/0000-0001-8607-0189 https://orcid.org/0000-0001-5629-4798 |
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| author | 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 Anderson, Daniel Griffith |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science 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 Anderson, Daniel Griffith |
| author_sort | Heartlein, Michael W. |
| collection | MIT |
| description | 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 |
| first_indexed | 2024-09-23T13:25:22Z |
| format | Article |
| id | mit-1721.1/119489 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:25:22Z |
| publishDate | 2018 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1194892022-10-01T15:11:12Z Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo 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 Anderson, Daniel Griffith 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 Kauffman, Kevin John Mir, Faryal Jhunjhunwala, Siddharth Kaczmarek, James Cliff Hurtado, Juan E. Yang, Jung H Webber, Matthew Kowalski, Piotr S Anderson, Daniel Griffith 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 Shire Pharmaceuticals 2018-12-07T20:38:44Z 2018-12-07T20:38:44Z 2016-09 2016-08 2018-12-04T13:37:46Z Article http://purl.org/eprint/type/JournalArticle 0142-9612 1878-5905 http://hdl.handle.net/1721.1/119489 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. https://orcid.org/0000-0002-9436-2453 https://orcid.org/0000-0001-8046-2288 https://orcid.org/0000-0002-6516-7499 https://orcid.org/0000-0003-0624-3532 https://orcid.org/0000-0001-8607-0189 https://orcid.org/0000-0001-5629-4798 http://dx.doi.org/10.1016/J.BIOMATERIALS.2016.09.006 Biomaterials Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | 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 Anderson, Daniel Griffith Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo |
| title | Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo |
| title_full | Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo |
| title_fullStr | Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo |
| title_full_unstemmed | Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo |
| title_short | Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo |
| title_sort | efficacy and immunogenicity of unmodified and pseudouridine modified mrna delivered systemically with lipid nanoparticles in vivo |
| url | http://hdl.handle.net/1721.1/119489 https://orcid.org/0000-0002-9436-2453 https://orcid.org/0000-0001-8046-2288 https://orcid.org/0000-0002-6516-7499 https://orcid.org/0000-0003-0624-3532 https://orcid.org/0000-0001-8607-0189 https://orcid.org/0000-0001-5629-4798 |
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