Broad-spectrum CRISPR-mediated inhibition of SARS-CoV-2 variants and endemic coronaviruses in vitro

Leiping Zeng, Yanxia Liu, Xammy Huu Nguyenla, Timothy R. Abbott, Mengting Han, Yanyu Zhu, Augustine Chemparathy, Xueqiu Lin, Xinyi Chen, Haifeng Wang, Draven A. Rane, Jordan M. Spatz, Saket Jain, Arjun Rustagi, Benjamin Pinsky, Adrianna E. Zepeda, Anastasia P. Kadina, John A. Walker, Kevin Holden, Nigel Temperton, Jennifer R. Cochran, Annelise E. Barron, Michael D. Connolly, Catherine A. Blish, David B. Lewis, Sarah A. Stanley (), Marie F. La Russa () and Lei S. Qi ()
Additional contact information
Leiping Zeng: Stanford University
Yanxia Liu: Stanford University
Xammy Huu Nguyenla: University of California
Timothy R. Abbott: Stanford University
Mengting Han: Stanford University
Yanyu Zhu: Stanford University
Augustine Chemparathy: Stanford University
Xueqiu Lin: Stanford University
Xinyi Chen: Stanford University
Haifeng Wang: Stanford University
Draven A. Rane: Stanford University
Jordan M. Spatz: Stanford University
Saket Jain: University of California San Francisco
Arjun Rustagi: Stanford University
Benjamin Pinsky: Stanford University
Adrianna E. Zepeda: Synthego Corporation
Anastasia P. Kadina: Synthego Corporation
John A. Walker: Synthego Corporation
Kevin Holden: Synthego Corporation
Nigel Temperton: Medway School of Pharmacy
Jennifer R. Cochran: Stanford University
Annelise E. Barron: Stanford University
Michael D. Connolly: Lawrence Berkeley National Laboratory
Catherine A. Blish: Stanford University
David B. Lewis: Stanford University
Sarah A. Stanley: University of California
Marie F. La Russa: Stanford University
Lei S. Qi: Stanford University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract A major challenge in coronavirus vaccination and treatment is to counteract rapid viral evolution and mutations. Here we demonstrate that CRISPR-Cas13d offers a broad-spectrum antiviral (BSA) to inhibit many SARS-CoV-2 variants and diverse human coronavirus strains with >99% reduction of the viral titer. We show that Cas13d-mediated coronavirus inhibition is dependent on the crRNA cellular spatial colocalization with Cas13d and target viral RNA. Cas13d can significantly enhance the therapeutic effects of diverse small molecule drugs against coronaviruses for prophylaxis or treatment purposes, and the best combination reduced viral titer by over four orders of magnitude. Using lipid nanoparticle-mediated RNA delivery, we demonstrate that the Cas13d system can effectively treat infection from multiple variants of coronavirus, including Omicron SARS-CoV-2, in human primary airway epithelium air-liquid interface (ALI) cultures. Our study establishes CRISPR-Cas13 as a BSA which is highly complementary to existing vaccination and antiviral treatment strategies.

Date: 2022
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DOI: 10.1038/s41467-022-30546-7

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