Simulation-Based Engineering of Time-Delayed Safety Switches for Safer Gene TherapiesClick to copy article linkArticle link copied!
- Helen Scott*Helen Scott*Email: [email protected]Raytheon BBN Technologies, Cambridge, Massachusetts 02138, United StatesMore by Helen Scott
- Dashan Sun*Dashan Sun*Email: [email protected]University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United StatesMore by Dashan Sun
- Jacob Beal*Jacob Beal*Email: [email protected]Raytheon BBN Technologies, Cambridge, Massachusetts 02138, United StatesMore by Jacob Beal
- Samira Kiani*Samira Kiani*Email: [email protected]Pittsburgh Liver Research Center, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United StatesDivision of Experimental Pathology, Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United StatesMcGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, United StatesMore by Samira Kiani
Abstract

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.
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