Genetic-code-expanded cell-based therapy for treating diabetes in mice
Genetic-code-expanded cell-based therapy for treating diabetes in mice
复制标题
用于治疗小鼠糖尿病的遗传密码扩展细胞疗法
DOI：
10.1038/s41589-021-00899-z
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发表时间：
2021-11-15
影响因子：
14.8
通讯作者：
Liu, Tao
中科院分区：
文献类型：
--
作者：
Chen, Chao;Yu, Guiling;Liu, Tao
诱导物触发的设计细胞治疗性蛋白表达是一种很有前途的疾病治疗策略。然而，由于大多数诱导系统利用转录机制，蛋白质表达时间框架不适合许多治疗应用。在这里，我们设计了一个基于遗传密码扩展的治疗系统，称为非规范氨基酸(NCAA)触发的治疗开关(NAT)，以在翻译水平上实现对同源NCAA的快速治疗性蛋白表达。NATS系统在触发后2 小时内显示出反应，而在基于转录机制的系统中没有检测到信号。此外，NatS系统与转录开关兼容，可进行多调节层控制。糖尿病小鼠体内植入NAT系统的微囊化细胞可在口服NCAA后90 分钟内缓解高血糖。我们还准备了含有NCAA的“饼干”，并在植入了NatS细胞的糖尿病小鼠中实现了长期的血糖控制。我们的概念验证研究证明了使用NatS系统来设计下一代基于细胞的疗法，以实现快速的口服诱导蛋白质表达。
Inducer-triggered therapeutic protein expression from designer cells is a promising strategy for disease treatment. However, as most inducer systems harness transcriptional machineries, protein expression timeframes are unsuitable for many therapeutic applications. Here, we engineered a genetic code expansion-based therapeutic system, termed noncanonical amino acids (ncAAs)-triggered therapeutic switch (NATS), to achieve fast therapeutic protein expression in response to cognate ncAAs at the translational level. The NATS system showed response within 2 hours of triggering, whereas no signal was detected in a transcription-machinery-based system. Moreover, NATS system is compatible with transcriptional switches for multi-regulatory-layer control. Diabetic mice with microencapsulated cell implants harboring the NATS system could alleviate hyperglycemia within 90 min on oral delivery of ncAA. We also prepared ncAA-containing ‘cookies’ and achieved long-term glycemic control in diabetic mice implanted with NATS cells. Our proof-of-concept study demonstrates the use of NATS system for the design of next-generation cell-based therapies to achieve fast orally induced protein expression.