Simulation-Based Engineering of Time-Delayed Safety Switches for Safer Gene Therapies.
Simulation-Based Engineering of Time-Delayed Safety Switches for Safer Gene Therapies.
复制标题
基于仿真的延时安全开关工程，实现更安全的基因治疗。
DOI：
10.1021/acssynbio.1c00621
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发表时间：
2022
影响因子：
4.7
通讯作者：
Kiani,Samira
中科院分区：
文献类型：
--
作者：
Scott,Helen;Sun,Dashan;Beal,Jacob;Kiani,Samira
基于CRISPR的基因编辑是一种强大的工具，在许多遗传性和获得性疾病的治疗中具有巨大的应用潜力。然而，CRISPR基因疗法在患者体内维持的时间越长，它导致有问题的副作用（如脱靶编辑或免疫反应）的可能性就越高。缓解这些问题的一种方法是将治疗系统的操作链接到安全开关，该安全开关自主地禁用其操作并在一段时间后移除所递送的治疗剂。在这里，我们提出了一个基于模拟的分析的潜力，用于调节这样的安全开关的时间延迟，使用一个或两个转录调节因子和/或重组酶。组合电路生成确定了30个潜在的架构，这样的电路，我们在仿真中评估的可调性，参数值的敏感性，和细胞到细胞的变化的敏感性。该模型预测这些电路架构之一具有所需的动态和鲁棒性，可以在CRISPR治疗的背景下进一步测试和应用。
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.