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

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

doi:10.1038/s41564-024-01726-6

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

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

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	2160-2172
Number of pages	13
Journal	Nature Microbiology
Volume	9
Issue number	8
DOIs	https://doi.org/10.1038/s41564-024-01726-6
State	Published - Aug 2024
Externally published	Yes

ASJC Scopus subject areas

Microbiology
Immunology
Applied Microbiology and Biotechnology
Genetics
Microbiology (medical)
Cell Biology

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10.1038/s41564-024-01726-6

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Basu, M., Zurla, C., Auroni, T. T., Vanover, D., Chaves, L. C. S., Sadhwani, H., Pathak, H., Basu, R., Beyersdorf, J. P., Amuda, O. O., Elsharkawy, A., Mosur, V., Arthur, R. A., Claussen, H., Sasser, L. E., Wroe, J. A., Peck, H. E., Kumar, M., Brinton, M. A., & Santangelo, P. J. (2024). mRNA-encoded Cas13 can be used to treat dengue infections in mice. Nature Microbiology, 9(8), 2160-2172. https://doi.org/10.1038/s41564-024-01726-6

Basu, M, Zurla, C, Auroni, TT, Vanover, D, Chaves, LCS, Sadhwani, H, Pathak, H, Basu, R, Beyersdorf, JP, Amuda, OO, Elsharkawy, A, Mosur, V, Arthur, RA, Claussen, H, Sasser, LE, Wroe, JA, Peck, HE, Kumar, M, Brinton, MA & Santangelo, PJ 2024, 'mRNA-encoded Cas13 can be used to treat dengue infections in mice', Nature Microbiology, vol. 9, no. 8, pp. 2160-2172. https://doi.org/10.1038/s41564-024-01726-6

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title = "mRNA-encoded Cas13 can be used to treat dengue infections in mice",

abstract = "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.",

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

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year = "2024",

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doi = "10.1038/s41564-024-01726-6",

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AU - Basu, Mausumi

AU - Zurla, Chiara

AU - Auroni, Tabassum T.

AU - Vanover, Daryll

AU - Chaves, Lorena C.S.

AU - Sadhwani, Heena

AU - Pathak, Heather

AU - Basu, Rahul

AU - Beyersdorf, Jared P.

AU - Amuda, Oluwatomi O.

AU - Elsharkawy, Amany

AU - Mosur, Varun

AU - Arthur, Robert A.

AU - Claussen, Henry

AU - Sasser, Loren E.

AU - Wroe, Jay A.

AU - Peck, Hannah E.

AU - Kumar, Mukesh

AU - Brinton, Margo A.

AU - Santangelo, Philip J.

PY - 2024/8

Y1 - 2024/8

N2 - 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.

AB - 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.

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

Abstract

ASJC Scopus subject areas

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