Genetically Encoded Protein Thermometer Enables Precise Electrothermal Control of Transgene Expression
Open Access
- 8 September 2021
- journal article
- research article
- Published by Wiley in Advanced Science
- Vol. 8 (21), 2101813
- https://doi.org/10.1002/advs.202101813
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.Funding Information
- H2020 European Research Council (785800)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (27449.2 PFLS‐LS)
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