Abstract:
:While the use of in vitro-transcribed mRNA (IVT-mRNA) in therapeutics is a rapidly expanding area, the transfection of the exogenous IVT-mRNA is accompanied by a risk of immune activation. This immunological defense mechanism suppresses cellular translation process and can reduce transfection efficiency to a considerable extent. In the present study, we investigated the in vitro effects of Integrated Stress Response Inhibitor (ISRIB), and dexamethasone, a steroidal anti-inflammatory drug, on the transfection activity of a lipid nanoparticle (LNP) that was composed of ionizable lipids and IVT-mRNA. In the case of transfection to mouse embryonic fibroblast (MEF) cells, ISRIB mainly enhanced the transfection activity at an early stage of transfection (0-6 h). In contrast, dexamethasone caused an increase in transfection activity at intermediate-late stages of transfection (4-48 h). We also investigated the in vivo effects of dexamethasone using an LNP on that the IVT-mRNA and lipid-conjugated dexamethasone (Dex-Pal) were co-loaded. The intravenous administration of the LNP successfully enhanced the protein expression in a mouse liver by up to 6.6-fold. Collectively, the co-delivery of an anti-inflammatory drug is a promising approach for enhancing transfection efficiency of IVT-mRNA.
journal_name
Biol Pharm Bulljournal_title
Biological & pharmaceutical bulletinauthors
Ohto T,Konishi M,Tanaka H,Onomoto K,Yoneyama M,Nakai Y,Tange K,Yoshioka H,Akita Hdoi
10.1248/bpb.b18-00783subject
Has Abstractpub_date
2019-01-01 00:00:00pages
299-302issue
2eissn
0918-6158issn
1347-5215journal_volume
42pub_type
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