Abstract
Next-generation gene and engineered-cell therapies benefit from incorporating synthetic gene networks that can precisely regulate the therapeutic output in response to externally administered signal inputs that are safe, readily bioavailable and pleasant to take. To enable such therapeutic control, a mammalian gene switch is designed to be responsive to the natural sweetener xylose and its functionality is assessed in mouse studies. The gene switch consists of the bacterial transcription regulator XylR fused to a mammalian transactivator, which binds to an optimized promoter in the presence of xylose, thereby allowing dose-dependent transgene expression. The sensitivity of SWEET (sweetener-inducible expression of transgene) is improved by coexpressing a xylose transporter. Mice implanted with encapsulated SWEET-engineered cells show increased blood levels of cargo protein when taking xylose-sweetened water or coffee, or highly concentrated apple extract, while they do not respond to intake of a usual amount of carrots, which contain xylose. In a proof-of-concept therapeutic application study, type-1 diabetic mice engineered with insulin-expressing SWEET show lowered glycemia and increased insulin levels when administered this fairly diabetic-compliant sweetener, compared to untreated mice. A SWEET-based therapy appears to have the potential to integrate seamlessly into patients' life-style and food habits in the move toward personalized medicine.