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Targeting herpes simplex virus with CRISPR–Cas9 cures herpetic stromal keratitis in mice

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  • Di Yin, Shanghai Jiao Tong University
  • ,
  • Sikai Ling, Shanghai Jiao Tong University
  • ,
  • Dawei Wang, Shanghai Jiao Tong University
  • ,
  • Yao Dai, Shanghai Jiao Tong University
  • ,
  • Hao Jiang, Fudan University, Guiyang Medical College
  • ,
  • Xujiao Zhou, Fudan University
  • ,
  • Soren R. Paludan
  • Jiaxu Hong, Fudan University, Guiyang Medical College
  • ,
  • Yujia Cai, Shanghai Jiao Tong University

Herpes simplex virus type 1 (HSV-1) is a leading cause of infectious blindness. Current treatments for HSV-1 do not eliminate the virus from the site of infection or latent reservoirs in the trigeminal ganglia. Here, we target HSV-1 genomes directly using mRNA-carrying lentiviral particles that simultaneously deliver SpCas9 mRNA and viral-gene-targeting guide RNAs (designated HSV-1-erasing lentiviral particles, termed HELP). We show that HELP efficiently blocks HSV-1 replication and the occurrence of herpetic stromal keratitis (HSK) in three different infection models. HELP was capable of eliminating the viral reservoir via retrograde transport from corneas to trigeminal ganglia. Additionally, HELP inhibited viral replication in human-derived corneas without causing off-target effects, as determined by whole-genome sequencing. These results support the potential clinical utility of HELP for treating refractory HSK.

TidsskriftNature Biotechnology
Sider (fra-til)567-577
Antal sider11
StatusUdgivet - maj 2021

Bibliografisk note

Funding Information:
We thank F. Zhang (MIT, USA) for reading and commenting on our manuscript. The work was supported by grants from the National Natural Science Foundation of China (31971364), the Pujiang Talent Project of Shanghai (18PJ1404500), the Natural Science Foundation of Shanghai (18ZR1419300) and startup funding from the Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University (WF220441504) to Y.C. and by the National Natural Science Foundation of China (81970766 and 81670818), the Shanghai Rising-Star Program (18QA1401100), the Shanghai Innovation Development Program (2020779) and the Shanghai Key Clinical Research Program (SHDC2020CR3052B) to J.H. S.R.P. is supported by the European Research Council (ERC-AdG ENVISION; 786602).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Copyright 2021 Elsevier B.V., All rights reserved.

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