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Simulation-Based Engineering of Time-Delayed Safety Switches for Safer Gene Therapies
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    Research Article

    Simulation-Based Engineering of Time-Delayed Safety Switches for Safer Gene Therapies
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    • Helen Scott*
      Helen Scott
      Raytheon BBN Technologies, Cambridge, Massachusetts 02138, United States
      *Email: [email protected]
      More by Helen Scott
    • Dashan Sun*
      Dashan Sun
      University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
      *Email: [email protected]
      More by Dashan Sun
    • Jacob Beal*
      Jacob Beal
      Raytheon BBN Technologies, Cambridge, Massachusetts 02138, United States
      *Email: [email protected]
      More by Jacob Beal
    • Samira Kiani*
      Samira Kiani
      Pittsburgh Liver Research Center, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
      Division of Experimental Pathology, Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
      McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, United States
      *Email: [email protected]
      More by Samira Kiani
    Other Access OptionsSupporting Information (3)

    ACS Synthetic Biology

    Cite this: ACS Synth. Biol. 2022, 11, 5, 1782–1789
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    https://doi.org/10.1021/acssynbio.1c00621
    Published April 12, 2022
    Copyright © 2022 American Chemical Society

    Abstract

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    CRISPR-based gene editing is a powerful tool with great potential for applications in the treatment of many inherited and acquired diseases. The longer that CRISPR gene therapy is maintained within a patient, however, the higher the likelihood that it will result in problematic side effects such as off-target editing or immune response. One approach to mitigating these issues is to link the operation of the therapeutic system to a safety switch that autonomously disables its operation and removes the delivered therapeutics after some amount of time. We present here a simulation-based analysis of the potential for regulating the time delay of such a safety switch using one or two transcriptional regulators and/or recombinases. Combinatorial circuit generation identifies 30 potential architectures for such circuits, which we evaluate in simulation with respect to tunability, sensitivity to parameter values, and sensitivity to cell-to-cell variation. This modeling predicts one of these circuit architectures to have the desired dynamics and robustness, which can be further tested and applied in the context of CRISPR therapeutics.

    Copyright © 2022 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acssynbio.1c00621.

    • Derivation of equations for CRISPR safety switches (presentation of the equations and architectures used for modeling the various designs for CRISPR safety switch circuits, parameter adjustment simulation results for all 30 candidate circuit architectures, and sensitivity analysis for the sequential activator to Cre-ON circuit with respect to each model parameter when configured for 5 day, 10 day, or 20 day delay) (PDF)

    • SBOL3 models of safety switch designs (TXT)

    • Matlab simulation files containing the ODE models for each CRISPR safety switch circuit (ZIP)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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    ACS Synthetic Biology

    Cite this: ACS Synth. Biol. 2022, 11, 5, 1782–1789
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acssynbio.1c00621
    Published April 12, 2022
    Copyright © 2022 American Chemical Society

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