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Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein

Lipid nanoparticles (LNPs) are the most clinically advanced delivery system for RNA-based drugs but have predominantly been investigated for intravenous and intramuscular administration. Subcutaneous administration opens the possibility of patient self-administration and hence long-term chronic trea...

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Autores principales: Davies, Nigel, Hovdal, Daniel, Edmunds, Nicholas, Nordberg, Peter, Dahlén, Anders, Dabkowska, Aleksandra, Arteta, Marianna Yanez, Radulescu, Aurel, Kjellman, Tomas, Höijer, Andreas, Seeliger, Frank, Holmedal, Elin, Andihn, Elisabeth, Bergenhem, Nils, Sandinge, Ann-Sofie, Johansson, Camilla, Hultin, Leif, Johansson, Marie, Lindqvist, Johnny, Björsson, Liselotte, Jing, Yujia, Bartesaghi, Stefano, Lindfors, Lennart, Andersson, Shalini
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039535/
https://www.ncbi.nlm.nih.gov/pubmed/33868782
http://dx.doi.org/10.1016/j.omtn.2021.03.008
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author Davies, Nigel
Hovdal, Daniel
Edmunds, Nicholas
Nordberg, Peter
Dahlén, Anders
Dabkowska, Aleksandra
Arteta, Marianna Yanez
Radulescu, Aurel
Kjellman, Tomas
Höijer, Andreas
Seeliger, Frank
Holmedal, Elin
Andihn, Elisabeth
Bergenhem, Nils
Sandinge, Ann-Sofie
Johansson, Camilla
Hultin, Leif
Johansson, Marie
Lindqvist, Johnny
Björsson, Liselotte
Jing, Yujia
Bartesaghi, Stefano
Lindfors, Lennart
Andersson, Shalini
author_facet Davies, Nigel
Hovdal, Daniel
Edmunds, Nicholas
Nordberg, Peter
Dahlén, Anders
Dabkowska, Aleksandra
Arteta, Marianna Yanez
Radulescu, Aurel
Kjellman, Tomas
Höijer, Andreas
Seeliger, Frank
Holmedal, Elin
Andihn, Elisabeth
Bergenhem, Nils
Sandinge, Ann-Sofie
Johansson, Camilla
Hultin, Leif
Johansson, Marie
Lindqvist, Johnny
Björsson, Liselotte
Jing, Yujia
Bartesaghi, Stefano
Lindfors, Lennart
Andersson, Shalini
author_sort Davies, Nigel
collection PubMed
description Lipid nanoparticles (LNPs) are the most clinically advanced delivery system for RNA-based drugs but have predominantly been investigated for intravenous and intramuscular administration. Subcutaneous administration opens the possibility of patient self-administration and hence long-term chronic treatment that could enable messenger RNA (mRNA) to be used as a novel modality for protein replacement or regenerative therapies. In this study, we show that subcutaneous administration of mRNA formulated within LNPs can result in measurable plasma exposure of a secreted protein. However, subcutaneous administration of mRNA formulated within LNPs was observed to be associated with dose-limiting inflammatory responses. To overcome this limitation, we investigated the concept of incorporating aliphatic ester prodrugs of anti-inflammatory steroids within LNPs, i.e., functionalized LNPs to suppress the inflammatory response. We show that the effectiveness of this approach depends on the alkyl chain length of the ester prodrug, which determines its retention at the site of administration. An unexpected additional benefit to this approach is the prolongation observed in the duration of protein expression. Our results demonstrate that subcutaneous administration of mRNA formulated in functionalized LNPs is a viable approach to achieving systemic levels of therapeutic proteins, which has the added benefits of being amenable to self-administration when chronic treatment is required.
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spelling pubmed-80395352021-04-16 Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein Davies, Nigel Hovdal, Daniel Edmunds, Nicholas Nordberg, Peter Dahlén, Anders Dabkowska, Aleksandra Arteta, Marianna Yanez Radulescu, Aurel Kjellman, Tomas Höijer, Andreas Seeliger, Frank Holmedal, Elin Andihn, Elisabeth Bergenhem, Nils Sandinge, Ann-Sofie Johansson, Camilla Hultin, Leif Johansson, Marie Lindqvist, Johnny Björsson, Liselotte Jing, Yujia Bartesaghi, Stefano Lindfors, Lennart Andersson, Shalini Mol Ther Nucleic Acids Original Article Lipid nanoparticles (LNPs) are the most clinically advanced delivery system for RNA-based drugs but have predominantly been investigated for intravenous and intramuscular administration. Subcutaneous administration opens the possibility of patient self-administration and hence long-term chronic treatment that could enable messenger RNA (mRNA) to be used as a novel modality for protein replacement or regenerative therapies. In this study, we show that subcutaneous administration of mRNA formulated within LNPs can result in measurable plasma exposure of a secreted protein. However, subcutaneous administration of mRNA formulated within LNPs was observed to be associated with dose-limiting inflammatory responses. To overcome this limitation, we investigated the concept of incorporating aliphatic ester prodrugs of anti-inflammatory steroids within LNPs, i.e., functionalized LNPs to suppress the inflammatory response. We show that the effectiveness of this approach depends on the alkyl chain length of the ester prodrug, which determines its retention at the site of administration. An unexpected additional benefit to this approach is the prolongation observed in the duration of protein expression. Our results demonstrate that subcutaneous administration of mRNA formulated in functionalized LNPs is a viable approach to achieving systemic levels of therapeutic proteins, which has the added benefits of being amenable to self-administration when chronic treatment is required. American Society of Gene & Cell Therapy 2021-03-13 /pmc/articles/PMC8039535/ /pubmed/33868782 http://dx.doi.org/10.1016/j.omtn.2021.03.008 Text en © 2021 AstraZeneca AB https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Davies, Nigel
Hovdal, Daniel
Edmunds, Nicholas
Nordberg, Peter
Dahlén, Anders
Dabkowska, Aleksandra
Arteta, Marianna Yanez
Radulescu, Aurel
Kjellman, Tomas
Höijer, Andreas
Seeliger, Frank
Holmedal, Elin
Andihn, Elisabeth
Bergenhem, Nils
Sandinge, Ann-Sofie
Johansson, Camilla
Hultin, Leif
Johansson, Marie
Lindqvist, Johnny
Björsson, Liselotte
Jing, Yujia
Bartesaghi, Stefano
Lindfors, Lennart
Andersson, Shalini
Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein
title Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein
title_full Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein
title_fullStr Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein
title_full_unstemmed Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein
title_short Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein
title_sort functionalized lipid nanoparticles for subcutaneous administration of mrna to achieve systemic exposures of a therapeutic protein
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039535/
https://www.ncbi.nlm.nih.gov/pubmed/33868782
http://dx.doi.org/10.1016/j.omtn.2021.03.008
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