瑞士巴塞尔大学的Martin Fussenegger研究组研发出一种人类转基因开关，其可通过感知冰凉来调控治疗性蛋白的产生。相关论文发表在2019年8月出版的《自然—医学》上。

使用简单的合成基因开关安全控制转基因表达的能力对于有效的基因和细胞疗法至关重要。研究人员利用人瞬时受体电位（TRP）melastatin 8（hTRPM8）（一种TRP通道家族成员）控制的信号通路来调控转基因的表达。人类TRPM8信号传导受薄荷醇（一种无害、天然、降温化合物）或暴露于凉爽环境（15-18°C）所调控。通过功能性地将hTRPM8诱导的信号转导至含有结合T细胞活化核因子元件的合成启动子，研究人员设计了合成基因回路，其可通过暴露于冷环境或薄荷醇来调节。结果表明，该基因开关在各种细胞类型和人原代细胞以及移植工程化细胞的小鼠中都有功能。通过响应薄荷醇的透皮递送，含有该基因回路的微囊化细胞植入物能够表达两种治疗性蛋白质中的任一种（胰岛素或经修饰的IIB型激活素受体配体捕获蛋白，mActRIIBECD-hFc），从而分别缓解四氧嘧啶处理后小鼠（1型糖尿病模型）的高血糖症，或者逆反地塞米松处理后小鼠（肌肉萎缩模型）的肌肉萎缩。

研究人员称，这种完全人源转基因开关将能够广泛地适用于临床应用。

附：英文原文

Title: A fully human transgene switch to regulate therapeutic protein production by cooling sensation

Author: Peng Bai, Ying Liu, Shuai Xue, Ghislaine Charpin-El Hamri, Pratik Saxena, Haifeng Ye, Mingqi Xie, Martin Fussenegger

Issue&Volume: Volume 25 Issue 8, August 2019

Abstract: The ability to safely control transgene expression with simple synthetic gene switches is critical for effective gene- and cell-based therapies. In the present study, the signaling pathway controlled by human transient receptor potential (TRP) melastatin 8 (hTRPM8), a TRP channel family member1, is harnessed to control transgene expression. Human TRPM8 signaling is stimulated by menthol, an innocuous, natural, cooling compound, or by exposure to a cool environment (1518C). By functionally linking hTRPM8-induced signaling to a synthetic promoter containing elements that bind nuclear factor of activated T cells, a synthetic gene circuit was designed that can be adjusted by exposure to either a cool environment or menthol. It was shown that this gene switch is functional in various cell types and human primary cells, as well as in mice implanted with engineered cells. In response to transdermal delivery of menthol, microencapsulated cell implants harboring this gene circuit, coupled to expression of either of two therapeutic proteins, insulin or a modified, activin type IIB, receptor ligand trap protein (mActRIIBECD-hFc), could alleviate hyperglycemia in alloxan-treated mice (a model of type 1 diabetes) or reverse muscle atrophy in dexamethasone-treated mice (a model of muscle wasting), respectively. This fully human-derived orthogonal transgene switch should be amenable to a wide range of clinical applications.

DOI: 10.1038/s41591-019-0501-8

Source:https://www.nature.com/articles/s41591-019-0501-8