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

Autor: Basu M; Department of Biology, Georgia State University, Atlanta, GA, USA., Zurla C; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA., Auroni TT; Department of Biology, Georgia State University, Atlanta, GA, USA., Vanover D; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA., Chaves LCS; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA., Sadhwani H; Department of Biology, Georgia State University, Atlanta, GA, USA., Pathak H; Department of Biology, Georgia State University, Atlanta, GA, USA., Basu R; Department of Biology, Georgia State University, Atlanta, GA, USA., Beyersdorf JP; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA., Amuda OO; Department of Biology, Georgia State University, Atlanta, GA, USA., Elsharkawy A; Department of Biology, Georgia State University, Atlanta, GA, USA., Mosur V; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA., Arthur RA; Emory Integrated Computational Core, Emory University, Atlanta, GA, USA., Claussen H; Emory Integrated Computational Core, Emory University, Atlanta, GA, USA., Sasser LE; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA., Wroe JA; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA., Peck HE; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA., Kumar M; Department of Biology, Georgia State University, Atlanta, GA, USA. mkumar8@gsu.edu., Brinton MA; Department of Biology, Georgia State University, Atlanta, GA, USA. mbrinton@gsu.edu., Santangelo PJ; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA. philip.j.santangelo@emory.edu.
Jazyk: angličtina
Zdroj: Nature microbiology [Nat Microbiol] 2024 Aug; Vol. 9 (8), pp. 2160-2172. Date of Electronic Publication: 2024 Jun 05.
DOI: 10.1038/s41564-024-01726-6
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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