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Development of an ObLiGaRe Doxycycline Inducible Cas9 system for pre-clinical cancer drug discovery

Author

Listed:
  • Anders Lundin

    (BioPharmaceuticals R&D, AstraZeneca)

  • Michelle J. Porritt

    (BioPharmaceuticals R&D, AstraZeneca)

  • Himjyot Jaiswal

    (BioPharmaceuticals R&D, AstraZeneca
    Cellink AB)

  • Frank Seeliger

    (BioPharmaceuticals R&D, AstraZeneca)

  • Camilla Johansson

    (BioPharmaceuticals R&D, AstraZeneca)

  • Abdel Wahad Bidar

    (BioPharmaceuticals R&D, AstraZeneca)

  • Lukas Badertscher

    (BioPharmaceuticals R&D, AstraZeneca)

  • Sandra Wimberger

    (BioPharmaceuticals R&D, AstraZeneca)

  • Emma J. Davies

    (Oncology R&D, AstraZeneca, Li KaShing Centre
    Healx)

  • Elizabeth Hardaker

    (Oncology R&D, AstraZeneca, Li KaShing Centre)

  • Carla P. Martins

    (Oncology R&D, AstraZeneca, Li KaShing Centre)

  • Emily James

    (Oncology R&D, AstraZeneca, Li KaShing Centre)

  • Therese Admyre

    (BioPharmaceuticals R&D, AstraZeneca)

  • Amir Taheri-Ghahfarokhi

    (BioPharmaceuticals R&D, AstraZeneca)

  • Jenna Bradley

    (BioPharmaceuticals R&D, AstraZeneca)

  • Anna Schantz

    (BioPharmaceuticals R&D, AstraZeneca)

  • Babak Alaeimahabadi

    (BioPharmaceuticals R&D, AstraZeneca)

  • Maryam Clausen

    (BioPharmaceuticals R&D, AstraZeneca)

  • Xiufeng Xu

    (BioPharmaceuticals R&D, AstraZeneca)

  • Lorenz M. Mayr

    (BioPharmaceuticals R&D, AstraZeneca)

  • Roberto Nitsch

    (BioPharmaceuticals R&D, AstraZeneca)

  • Mohammad Bohlooly-Y

    (BioPharmaceuticals R&D, AstraZeneca)

  • Simon T. Barry

    (Oncology R&D, AstraZeneca, Li KaShing Centre)

  • Marcello Maresca

    (BioPharmaceuticals R&D, AstraZeneca)

Abstract

The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.

Suggested Citation

  • Anders Lundin & Michelle J. Porritt & Himjyot Jaiswal & Frank Seeliger & Camilla Johansson & Abdel Wahad Bidar & Lukas Badertscher & Sandra Wimberger & Emma J. Davies & Elizabeth Hardaker & Carla P. M, 2020. "Development of an ObLiGaRe Doxycycline Inducible Cas9 system for pre-clinical cancer drug discovery," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18548-9
    DOI: 10.1038/s41467-020-18548-9
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    Cited by:

    1. Elizabeth L. Hardaker & Emilio Sanseviero & Ankur Karmokar & Devon Taylor & Marta Milo & Chrysis Michaloglou & Adina Hughes & Mimi Mai & Matthew King & Anisha Solanki & Lukasz Magiera & Ricardo Miraga, 2024. "The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Dmitrii Degtev & Jack Bravo & Aikaterini Emmanouilidi & Aleksandar Zdravković & Oi Kuan Choong & Julia Liz Touza & Niklas Selfjord & Isabel Weisheit & Margherita Francescatto & Pinar Akcakaya & Michel, 2024. "Engineered PsCas9 enables therapeutic genome editing in mouse liver with lipid nanoparticles," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Alice Fletcher & Dean Clift & Emma Vries & Sergio Martinez Cuesta & Timothy Malcolm & Francesco Meghini & Raghothama Chaerkady & Junmin Wang & Abby Chiang & Shao Huan Samuel Weng & Jonathan Tart & Edm, 2023. "A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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