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

• Main Authors: Hanne Huysmans (Author), Zifu Zhong (Author), Joyca De Temmerman (Author), Barbara L. Mui (Author), Ying K. Tam (Author), Séan Mc Cafferty (Author), Arlieke Gitsels (Author), Daisy Vanrompay (Author), Niek N. Sanders (Author)
• Format: Book
• Published: Elsevier, 2019-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

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. Keywords: self-amplifying mRNA, pDNA, non-replicating mRNA, lipid nanoparticles, innate immune response, electroporation, intradermal, expression kinetics, mice

Item Description

2162-2531
10.1016/j.omtn.2019.08.001