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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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    as
    1. Shuofeng Yuan & Xin Yin & Xiangzhi Meng & Jasper Fuk-Woo Chan & Zi-Wei Ye & Laura Riva & Lars Pache & Chris Chun-Yiu Chan & Pok-Man Lai & Chris Chung-Sing Chan & Vincent Kwok-Man Poon & Andrew Chak-Yi, 2021. "Clofazimine broadly inhibits coronaviruses including SARS-CoV-2," Nature, Nature, vol. 593(7859), pages 418-423, May.
    2. Mohamed Fareh & Wei Zhao & Wenxin Hu & Joshua M. L. Casan & Amit Kumar & Jori Symons & Jennifer M. Zerbato & Danielle Fong & Ilia Voskoboinik & Paul G. Ekert & Rajeev Rudraraju & Damian F. J. Purcell , 2021. "Reprogrammed CRISPR-Cas13b suppresses SARS-CoV-2 replication and circumvents its mutational escape through mismatch tolerance," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Delphine Planas & David Veyer & Artem Baidaliuk & Isabelle Staropoli & Florence Guivel-Benhassine & Maaran Michael Rajah & Cyril Planchais & Françoise Porrot & Nicolas Robillard & Julien Puech & Matth, 2021. "Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization," Nature, Nature, vol. 596(7871), pages 276-280, August.
    4. Dami A. Collier & Anna Marco & Isabella A. T. M. Ferreira & Bo Meng & Rawlings P. Datir & Alexandra C. Walls & Steven A. Kemp & Jessica Bassi & Dora Pinto & Chiara Silacci-Fregni & Siro Bianchi & M. A, 2021. "Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies," Nature, Nature, vol. 593(7857), pages 136-141, May.
    5. Pengfei Wang & Manoj S. Nair & Lihong Liu & Sho Iketani & Yang Luo & Yicheng Guo & Maple Wang & Jian Yu & Baoshan Zhang & Peter D. Kwong & Barney S. Graham & John R. Mascola & Jennifer Y. Chang & Mich, 2021. "Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7," Nature, Nature, vol. 593(7857), pages 130-135, May.
    6. Goran Kokic & Hauke S. Hillen & Dimitry Tegunov & Christian Dienemann & Florian Seitz & Jana Schmitzova & Lucas Farnung & Aaron Siewert & Claudia Höbartner & Patrick Cramer, 2021. "Mechanism of SARS-CoV-2 polymerase stalling by remdesivir," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
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