Journal Article

FZJ-2021-01724

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein

Davies, N. (Corresponding author) ; Hovdal, D. ; Edmunds, N. ; Nordberg, P. ; Dahlén, A. ; Dabkowska, A. ; Arteta, M. Y. ; Radulescu, A.FZJ* ; Kjellman, T. ; Höijer, A. ; Seeliger, F. ; Holmedal, E. ; Andihn, E. ; Bergenhem, N. ; Sandinge, A.-S. ; Johansson, C. ; Hultin, L. ; Johansson, M. ; Lindqvist, J. ; Björsson, L. ; Jing, Y. ; Bartesaghi, S. ; Lindfors, L. ; Andersson, S.

2021
Nature Publ. Group New York, NY

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Please use a persistent id in citations: http://hdl.handle.net/2128/27607  doi:10.1016/j.omtn.2021.03.008

Abstract: 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.

Keyword(s): Health and Life (1st) ; Biology (2nd) ; Medicine (2nd) ; Soft Condensed Matter (2nd)

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Contributing Institute(s):

1. JCNS-FRM-II (JCNS-FRM-II)
2. Heinz Maier-Leibnitz Zentrum (MLZ)
3. Neutronenstreuung (JCNS-1)
4. JCNS-4 (JCNS-4)

Research Program(s):

1. 6G4 - Jülich Centre for Neutron Research (JCNS) (FZJ) (POF4-6G4) (POF4-6G4)
2. 632 - Materials – Quantum, Complex and Functional Materials (POF4-632) (POF4-632)

Experiment(s):

1. KWS-2: Small angle scattering diffractometer (NL3ao)

Appears in the scientific report 2021

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