mRNA-encoded Cas13 can be used to treat dengue infections in mice

期刊论文
发表日期：

2024年6月5日

查看全文

Mausumi Basu,
Chiara Zurla,
Tabassum T. Auroni,
Daryll Vanover,
Lorena C. S. Chaves,
Heena Sadhwani,
Heather Pathak,
Rahul Basu,
Jared P. Beyersdorf,
Oluwatomi O. Amuda,
Amany Elsharkawy,
Varun Mosur,
Robert A. Arthur,
Henry Claussen,
Loren E. Sasser,
Jay A. Wroe,
Hannah E. Peck,
Mukesh Kumar,
Margo A. Brinton,
Philip J. Santangelo

摘要

Dengue is a major global health threat, and there are no approved antiviral agents. Prior research using Cas13 only demonstrated dengue mitigation in vitro. Here we demonstrate that systemic delivery of mRNA-encoded Cas13a and guide RNAs formulated in lipid nanoparticles can be used to treat dengue virus (DENV) 2 and 3 in mice. First, we identified guides against DENV 2 and 3 that demonstrated in vitro efficacy. Next, we confirmed that Cas13 enzymatic activity is necessary for DENV 2 or DENV 3 mitigation in vitro. Last, we show that a single dose of lipid-nanoparticle-formulated mRNA-encoded Cas13a and guide RNA, administered 1 day post-infection, promotes survival of all infected animals and serum viral titre decreases on days 2 and 3 post-infection after lethal challenge in mice. Off-target analysis in mice using RNA sequencing showed no collateral cleavage. Overall, these data demonstrate the potential of mRNA-encoded Cas13 as a pan-DENV drug.