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

Author

Listed:
  • 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
    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
    Chan Zuckerberg BioHub)

  • David B. Lewis

    (Stanford University)

  • Sarah A. Stanley

    (University of California)

  • Marie F. La Russa

    (Stanford University)

  • Lei S. Qi

    (Stanford University
    Chan Zuckerberg BioHub
    Stanford University)

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.

Suggested Citation

  • 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 & Sake, 2022. "Broad-spectrum CRISPR-mediated inhibition of SARS-CoV-2 variants and endemic coronaviruses in vitro," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30546-7
    DOI: 10.1038/s41467-022-30546-7
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