TY  - JOUR
AU  - Davies, Nigel
AU  - Hovdal, Daniel
AU  - Edmunds, Nicholas
AU  - Nordberg, Peter
AU  - Dahlén, Anders
AU  - Dabkowska, Aleksandra
AU  - Arteta, Marianna Yanez
AU  - Radulescu, Aurel
AU  - Kjellman, Tomas
AU  - Höijer, Andreas
AU  - Seeliger, Frank
AU  - Holmedal, Elin
AU  - Andihn, Elisabeth
AU  - Bergenhem, Nils
AU  - Sandinge, Ann-Sofie
AU  - Johansson, Camilla
AU  - Hultin, Leif
AU  - Johansson, Marie
AU  - Lindqvist, Johnny
AU  - Björsson, Liselotte
AU  - Jing, Yujia
AU  - Bartesaghi, Stefano
AU  - Lindfors, Lennart
AU  - Andersson, Shalini
TI  - Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein
JO  - Molecular Therapy / Nucleic Acids
VL  - 24
SN  - 2162-2531
CY  - New York, NY
PB  - Nature Publ. Group
M1  - FZJ-2021-01724
SP  - 369 - 384
PY  - 2021
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 33868782
UR  - <Go to ISI:>//WOS:000658506500001
DO  - DOI:10.1016/j.omtn.2021.03.008
UR  - https://juser.fz-juelich.de/record/891766
ER  -