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A simeprevir-inducible molecular switch for the control of cell and gene therapies

Author

Listed:
  • Stacey E. Chin

    (Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca)

  • Christina Schindler

    (Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca)

  • Lisa Vinall

    (Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca)

  • Roger B. Dodd

    (Biologics Engineering, Oncology R&D, AstraZeneca)

  • Lisa Bamber

    (Biologics Engineering, Oncology R&D, AstraZeneca)

  • Sandrine Legg

    (Biologics Engineering, Oncology R&D, AstraZeneca)

  • Anna Sigurdardottir

    (Biologics Engineering, Oncology R&D, AstraZeneca)

  • D. Gareth Rees

    (Biologics Engineering, Oncology R&D, AstraZeneca)

  • Tim I. M. Malcolm

    (Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca)

  • Samantha J. Spratley

    (Biologics Engineering, Oncology R&D, AstraZeneca)

  • Cecilia Granéli

    (Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca)

  • Jonathan Sumner

    (Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca)

  • Natalie J. Tigue

    (Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca)

Abstract

Chemical inducer of dimerization (CID) modules can be used effectively as molecular switches to control biological processes, and thus there is significant interest within the synthetic biology community in identifying novel CID systems. To date, CID modules have been used primarily in engineering cells for in vitro applications. To broaden their utility to the clinical setting, including the potential to control cell and gene therapies, the identification of novel CID modules should consider factors such as the safety and pharmacokinetic profile of the small molecule inducer, and the orthogonality and immunogenicity of the protein components. Here we describe a CID module based on the orally available, approved, small molecule simeprevir and its target, the NS3/4A protease from hepatitis C virus. We demonstrate the utility of this CID module as a molecular switch to control biological processes such as gene expression and apoptosis in vitro, and show that the CID system can be used to rapidly induce apoptosis in tumor cells in a xenograft mouse model, leading to complete tumor regression.

Suggested Citation

  • Stacey E. Chin & Christina Schindler & Lisa Vinall & Roger B. Dodd & Lisa Bamber & Sandrine Legg & Anna Sigurdardottir & D. Gareth Rees & Tim I. M. Malcolm & Samantha J. Spratley & Cecilia Granéli & J, 2023. "A simeprevir-inducible molecular switch for the control of cell and gene therapies," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43484-9
    DOI: 10.1038/s41467-023-43484-9
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    References listed on IDEAS

    as
    1. Zhong Guo & Oleh Smutok & Wayne A. Johnston & Patricia Walden & Jacobus P. J. Ungerer & Thomas S. Peat & Janet Newman & Jake Parker & Tom Nebl & Caryn Hepburn & Artem Melman & Richard J. Suderman & Ev, 2021. "Design of a methotrexate-controlled chemical dimerization system and its use in bio-electronic devices," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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