Cas13d knockdown of lung protease Ctsl prevents and treats SARS-CoV-2 infection

Zhifen Cui, Cong Zeng, Furong Huang, Fuwen Yuan, Jingyue Yan, Yue Zhao, Yufan Zhou, William Hankey, Victor X. Jin, Jiaoti Huang, Herman F. Staats, Jeffrey I. Everitt, Gregory D. Sempowski, Hongyan Wang, Yizhou Dong, Shan Lu Liu, Qianben Wang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

SARS-CoV-2 entry into cells requires specific host proteases; however, no successful in vivo applications of host protease inhibitors have yet been reported for treatment of SARS-CoV-2 pathogenesis. Here we describe a chemically engineered nanosystem encapsulating CRISPR–Cas13d, developed to specifically target lung protease cathepsin L (Ctsl) messenger RNA to block SARS-CoV-2 infection in mice. We show that this nanosystem decreases lung Ctsl expression in normal mice efficiently, specifically and safely. We further show that this approach extends survival of mice lethally infected with SARS-CoV-2, correlating with decreased lung virus burden, reduced expression of proinflammatory cytokines/chemokines and diminished severity of pulmonary interstitial inflammation. Postinfection treatment by this nanosystem dramatically lowers the lung virus burden and alleviates virus-induced pathological changes. Our results indicate that targeting lung protease mRNA by Cas13d nanosystem represents a unique strategy for controlling SARS-CoV-2 infection and demonstrate that CRISPR can be used as a potential treatment for SARS-CoV-2 infection. [Figure not available: see fulltext.].

Original languageEnglish (US)
JournalNature Chemical Biology
DOIs
StateAccepted/In press - 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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