Genetically Encoded Protein Thermometer Enables Precise Electrothermal Control of Transgene Expression

Advanced Science

Ghislaine Charpin‐El Hamri¹  Krzysztof Krawczyk²  Bozhidar‐Adrian Stefanov²  Martin Fussenegger²  Maysam Mansouri²  Adrian Bertschi²  Ana P. Teixeira²  Shuai Xue² 

[1] Département Génie Biologique Institut Universitaire de Technologie Villeurbanne Cedex F‐69622 France;ETH Zürich Department of Biosystems Science and Engineering Mattenstrasse 26 Basel 4058 Switzerland;

关键词: diabetes;    gene regulation;    gene switches;    synthetic biology;    temperature;   

DOI  :  10.1002/advs.202101813

来源: DOAJ

【 摘 要 】

Abstract Body temperature is maintained at around 37 °C in humans, but may rise to 40 °C or more during high‐grade fever, which occurs in most adults who are seriously ill. However, endogenous temperature sensors, such as ion channels and heat‐shock promoters, are fully activated only at noxious temperatures above this range, making them unsuitable for medical applications. Here, a genetically encoded protein thermometer (human enhanced gene activation thermometer; HEAT) is designed that can trigger transgene expression in the range of 37–40 °C by linking a mutant coiled‐coil temperature‐responsive protein sensor to a synthetic transcription factor. To validate the construct, a HEAT‐transgenic monoclonal human cell line, FeverSense, is generated and it is confirmed that it works as a fever sensor that can temperature‐ and exposure‐time‐dependently trigger reporter gene expression in vitro and in vivo. For translational proof of concept, microencapsulated designer cells stably expressing a HEAT‐controlled insulin production cassette in a mouse model of type‐1 diabetes are subcutaneously implanted and topical heating patches are used to apply heat corresponding to a warm sensation in humans. Insulin release is induced, restoring normoglycemia. Thus, HEAT appears to be suitable for practical electrothermal control of cell‐based therapy, and may also have potential for next‐generation treatment of fever‐associated medical conditions.

【 授权许可】

Unknown