Biologic drug therapies are increasingly used for inflammatory diseases such as rheumatoid arthritis but may cause significant adverse effects when delivered continuously at high doses. We used CRISPR-Cas9 genome editing of iPSCs to create a synthetic gene circuit that senses changing levels of endogenous inflammatory cytokines to trigger a proportional therapeutic response. Cells were engineered into cartilaginous constructs that showed rapid activation and recovery in response to inflammation in vitro or in vivo. In the murine K/BxN model of inflammatory arthritis, bioengineered implants significantly mitigated disease severity as measured by joint pain, structural damage, and systemic and local inflammation. Therapeutic implants completely prevented increased pain sensitivity and bone erosions, a feat not achievable by current clinically available disease-modifying drugs. Combination tissue engineering and synthetic biology promises a range of potential applications for treating chronic diseases via custom-designed cells that express therapeutic transgenes in response to dynamically changing biological signals.

中文翻译：

---

用于自动调节抗细胞因子药物输送的基因组工程生物人工植入物

生物药物疗法越来越多地用于类风湿性关节炎等炎症性疾病，但如果持续以高剂量给药，可能会导致严重的不良反应。我们使用 iPSC 的 CRISPR-Cas9 基因组编辑来创建一个合成基因回路，该回路可感知内源性炎症细胞因子水平的变化，从而触发成比例的治疗反应。细胞被设计成软骨结构，在体外或体内显示出对炎症的快速激活和恢复。在炎症性关节炎的小鼠 K/BxN 模型中，生物工程植入物显着减轻了关节疼痛、结构损伤以及全身和局部炎症所衡量的疾病严重程度。治疗性植入物完全防止了疼痛敏感性增加和骨侵蚀，目前临床上可用的疾病缓解药物无法实现的壮举。组织工程和合成生物学的结合有望通过定制设计的细胞治疗慢性病的一系列潜在应用，这些细胞表达治疗性转基因以响应动态变化的生物信号。