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

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. Martins, Emily James, Therese Admyre, Amir Taheri-Ghahfarokhi, Jenna Bradley, Anna Schantz, Babak Alaeimahabadi, Maryam Clausen, Xiufeng Xu, Lorenz M. Mayr, Roberto Nitsch, Mohammad Bohlooly-Y, Simon T. Barry and Marcello Maresca ()
Additional contact information
Anders Lundin: BioPharmaceuticals R&D, AstraZeneca
Michelle J. Porritt: BioPharmaceuticals R&D, AstraZeneca
Himjyot Jaiswal: BioPharmaceuticals R&D, AstraZeneca
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
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

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18548-9

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