Expression Kinetics and Innate Immune Response after Electroporation and LNP-Mediated Delivery of a Self-Amplifying mRNA in the Skin

In this work, we studied the expression kinetics and innate immune response of a self-amplifying mRNA (sa-RNA) after electroporation and lipid-nanoparticle (LNP)-mediated delivery in the skin of mice. Intradermal electroporation of the sa-RNA resulted in a plateau-shaped expression, with the plateau...

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Bibliographic Details
Published in:Molecular therapy. Nucleic acids 2019-09, Vol.17, p.867-878
Main Authors: Huysmans, Hanne, Zhong, Zifu, De Temmerman, Joyca, Mui, Barbara L., Tam, Ying K., Mc Cafferty, Séan, Gitsels, Arlieke, Vanrompay, Daisy, Sanders, Niek N.
Format: Article
Language:English
Subjects:
Antigens
Apoptosis
DNA biosynthesis
Electroporation
Experiments
expression kinetics
Immune response
Immune system
Injection
Injections
innate immune response
Innate immunity
intradermal
Kinases
lipid nanoparticles
Lipids
Lymph nodes
mice
mRNA
Nanoparticles
non-replicating mRNA
pDNA
Proteins
self-amplifying mRNA
Software
Statistical analysis
β-Interferon
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Summary:In this work, we studied the expression kinetics and innate immune response of a self-amplifying mRNA (sa-RNA) after electroporation and lipid-nanoparticle (LNP)-mediated delivery in the skin of mice. Intradermal electroporation of the sa-RNA resulted in a plateau-shaped expression, with the plateau between day 3 and day 10. The overall protein expression of sa-RNA was significantly higher than that obtained after electroporation of plasmid DNA (pDNA) or non-replication mRNAs. Moreover, using IFN-β reporter mice, we elucidated that intradermal electroporation of sa-RNA induced a short-lived moderate innate immune response, which did not affect the expression of the sa-RNA. A completely different expression profile and innate immune response were observed when LNPs were used. The expression peaked 24 h after intradermal injection of sa-RNA-LNPs and subsequently showed a sharp drop. This drop might be explained by a translational blockage caused by the strong innate immune response that we observed in IFN-β reporter mice shortly (4 h) after intradermal injection of sa-RNA-LNPs. A final interesting observation was the capacity of sa-RNA-LNPs to transfect the draining lymph nodes after intradermal injection. [Display omitted]
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2019.08.001