In vivo CRISPR editing without detectable off-target mutations at the genome level

Science



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  1. Current address: Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

  2. Current address: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy

  3. Current address: Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA

  4. Current Address: GE Healthcare Life Sciences, The Grove Center, Amersham, United Kingdom

  5. These authors contributed equally: Pinar Akcakaya, Maggie L. Bobbin

Affiliations

  1. Discovery Biology, Discovery Sciences, IMED Biotechnology Unit, AstraZeneca, Gothenburg, Sweden

    • Pinar Akcakaya
    • , Michelle J. Porritt
    • , Alba Carreras
    • , Tania Baccega
    • , Mikael Bjursell
    • , Lorenz M. Mayr
    • , Mohammad Bohlooly-Y
    • & Marcello Maresca

  2. Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    • Maggie L. Bobbin
    • , Jimmy A. Guo
    • , Jose Malagon-Lopez
    • , Kendell Clement
    • , Sara P. Garcia
    • , Shengdar Q. Tsai
    • , Nhu T. Nguyen
    • , Luca Pinello
    • Martin J. Aryee
    • & J. Keith Joung

  3. Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    • Maggie L. Bobbin
    • , Jimmy A. Guo
    • , Jose Malagon-Lopez
    • , Kendell Clement
    • , Shengdar Q. Tsai
    • , Nhu T. Nguyen
    • & J. Keith Joung

  4. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    • Maggie L. Bobbin
    • , Jose Malagon-Lopez
    • , Kendell Clement
    • , Shengdar Q. Tsai
    • , Luca Pinello
    • Martin J. Aryee
    • & J. Keith Joung

  5. Advanced Medicines Safety, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom

  6. Quantitative Biology, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom

  7. Pathology Science, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

  8. Advanced Medicines Safety, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

authors

  1. Search Pinar Akcakaya at:

  2. Search for Maggie L. Bobbin at:

  3. Search for Jimmy A. Guo at:

  4. Search for Jose Malagon-Lopez at:

  5. Search for Kendell Clement at:

  6. Search for Sara P. Garcia at:

  7. Search for Mick D. Fellows in:

  8. Search for Michelle J. Porritt at:

  9. Search for Mike A. Firth at:

  10. Search Alba Carreras at:

  11. Search for Tania Baccega at:

  12. Search for Frank Seeliger in:

  13. Search for Mikael Bjursell at:

  14. Search Shengdar Q. Tsai at:

  15. Search for Nhu T. Nguyen at:

  16. Search Roberto Nitsch at:

  17. Search Lorenz M. Mayr at:

  18. Locate Luca Pinello at:

  19. Search for Mohammad Bohlooly-Y at:

  20. Search for Martin J. Aryee in:

  21. Search Marcello Maresca at:

  22. Search for Keith Joung at:

contributions

P.A., M.J.P., T.B. and M.B. intravenous caudal vein injections performed. PENNSYLVANIA. and T.B. coordinated blood sampling of saphenous vein and plasma extractions. P.A., M.J.P., A.C., T.B., M.B., M.M. and R.N. performed in vivo terminations and organ harvesting. PENNSYLVANIA. have conducted Surveyor tests for genomic DNA from mouse livers. PENNSYLVANIA. and T.B. ELISA for the detection of Pcsk9 protein in plasma samples. M.L.B., J.A.G., S.Q.T. and N.T.N. performed the amplicon sequencing experiments targeted by CIRCLE-seq and. J.M.-L., K.C., S.P.G., L.P. and M.J.A. performed bioinformatic and computational analyzes of off-target experiments. MY F. Generation of AstraZeneca proprietary software for the identification of rRNAs. PENNSYLVANIA. designed ARNGs with the help of M.A.F., and validated their functional activity. F.S. phenotypic characterization of the mouse. P.A., M.L.B., S.Q.T., M.M., M.B.-Y, A.C., R.N., M.D.F., L.M.M. and J.K.J. designed and designed the study. P.A., M.L.B., M.M. and J.K.J. organized and supervised experiences. P.A., M.L.B., J.A.G., M.M. and J.K.J. prepared the manuscript with the contribution of all the authors.

Competing interests

J.K.J. holds financial interests in Beam Therapeutics, Blink Therapeutics, Editas Medicine, Endcadia, Monitor Biotechnology (formerly Beacon Genomics), Pairwise Plants, Poseida Therapeutics and Transposagen Biopharmaceuticals. M.J.A. and S.Q.T. have financial interests in Monitor Biotechnologies. The interests of J.K.J. and M.J.A. have been reviewed and managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. S.Q.T. and J.K.J. are co-inventors on a patent describing the CIRCLE-seq method. P.A., M.D.F., M.J.P., M.A.F., F.S., M.B., R.N., M.B.Y. and Mr. M. are employees and shareholders of AstraZeneca. L.M.M. is an employee and shareholder of GE Healthcare and shareholder of AstraZeneca.

Corresponding authors

Correspondence to
Marcello Maresca or J. Keith Joung.

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