ABSTRACT
Dynamically adjustable gene- and cell-based therapies are recognized as next-generation medicine. However, the translation of precision therapies into clinics is limited by lack of specific switches controlled by inducers that are safe and ready for clinical use. Ferulic acid (FA) is a phytochemical with a wide range of therapeutic effects, and its salt sodium ferulate (SF) is used as an antithrombotic drug in clinics. Here, we describe an FA/SF-adjustable transcriptional switch controlled by the clinically licensed drug SF. We demonstrated that SF-responsive switches can be engineered to control CRISPR-Cas9 systems for on-command genome/epigenome engineering. In addition, we integrated FA-controlled switches into programmable biocomputers to process logic operations. We further demonstrated the dose-dependent SF-inducible transgene expression in mice by oral administration of SF tablets. Engineered switches responsive to small-molecule clinically licensed drugs to achieve adjustable transgene expression profiles provide new opportunities for dynamic interventions in gene- and cell-based precision medicine.
Subject(s)
Gene Expression Regulation , Mammals , Animals , Coumaric Acids , HeLa Cells , Humans , Mice , TransgenesABSTRACT
With the increasingly dominant role of smartphones in our lives, mobile health care systems integrating advanced point-of-care technologies to manage chronic diseases are gaining attention. Using a multidisciplinary design principle coupling electrical engineering, software development, and synthetic biology, we have engineered a technological infrastructure enabling the smartphone-assisted semiautomatic treatment of diabetes in mice. A custom-designed home server SmartController was programmed to process wireless signals, enabling a smartphone to regulate hormone production by optically engineered cells implanted in diabetic mice via a far-red light (FRL)-responsive optogenetic interface. To develop this wireless controller network, we designed and implanted hydrogel capsules carrying both engineered cells and wirelessly powered FRL LEDs (light-emitting diodes). In vivo production of a short variant of human glucagon-like peptide 1 (shGLP-1) or mouse insulin by the engineered cells in the hydrogel could be remotely controlled by smartphone programs or a custom-engineered Bluetooth-active glucometer in a semiautomatic, glucose-dependent manner. By combining electronic device-generated digital signals with optogenetically engineered cells, this study provides a step toward translating cell-based therapies into the clinic.
