Cas13d knockdown of lung protease Ctsl prevents and treats SARS-CoV-2 infection. Nat Chem Biol 2022 Oct;18(10):1056-1064
Date
07/26/2022Pubmed ID
35879545Pubmed Central ID
PMC10082993DOI
10.1038/s41589-022-01094-4Scopus ID
2-s2.0-85134648919 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
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.
Author List
Cui Z, Zeng C, Huang F, Yuan F, Yan J, Zhao Y, Zhou Y, Hankey W, Jin VX, Huang J, Staats HF, Everitt JI, Sempowski GD, Wang H, Dong Y, Liu SL, Wang QAuthor
Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCathepsin L
Chemokines
Cytokines
Endopeptidases
Lung
Mice
Peptide Hydrolases
Protease Inhibitors
RNA, Messenger
