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通过临床许可的葡萄酸盐调节转基因表达的分子开关的演变

Ana Palma Teixeira¹, Shuai Xue¹, Jinbo Huang¹

¹Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058Basel, Switzerland.

Nucleic acids research

|July 27, 2023

概括

合成生物学使用工程制造的葡萄糖酸盐敏感开关来推进基因疗法控制. 这些开关调节小鼠的治疗性蛋白质生产,恢复1型糖尿病模型中的正常血糖水平.

科学领域:

合成生物学合成生物学
基因工程是一种基因工程.
分子生物学分子生物学

背景情况:

合成生物学为基因和细胞疗法提供了精确的控制.
小分子可以作为治疗性基因表达的诱导剂.
开发安全有效的分子开关对于先进的疗法至关重要.

研究的目的:

设计用于转基因表达控制的新型葡萄糖酸盐敏感遗传开关.
测试这些开关在哺乳动物细胞和体内细胞中的有效性.
为了证明这些开关在治疗性蛋白质生产中的潜力.

主要方法:

组装的基于葡萄糖酸反应转录抑制器 (GntR) 的开关.
重新连接了GntRDNA结合,并利用其二分化来激活基因.
采用随机突变发生和查来增强开关功能.
在细胞培养,封装细胞和转基因小鼠中验证了开关.

主要成果:

开发了功能性的OFF和ON类型的葡萄酸盐开关.
设计了增强的GntR变体,并创建了双输入逻辑门.
在小鼠体内证明了转基因表达的调节.
在1型糖尿病小鼠中通过葡萄糖酸诱导的胰岛素分泌成功恢复了正常血糖.

结论:

经过工程设计的对葡萄糖酸盐敏感的开关可以对转基因表达提供强大的控制.
这些合成遗传装置在体外和体内环境中都有效.
口服葡萄糖酸可以调节局部治疗性蛋白质的生产,显示了1型糖尿病治疗的前景.

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