Tuning the Response of Synthetic Mechanogenetic Gene Circuits Using Mutations in TRPV4.

Conventional gene therapy approaches for drug delivery generally rely on constitutive expression of the transgene and thus lack precise control over the timing and magnitude of delivery. Synthetic gene circuits with promoters that are responsive to user-defined stimuli can provide a molecular switch that can be utilized by cells to control drug production. Our laboratory has previously developed a mechanogenetic gene circuit that can deliver biological drugs, such as interleukin-1 receptor antagonist (IL-1Ra), on-demand through the activation of Transient receptor potential family, vanilloid 4 (TRPV4), a mechanosensory ion channel that has been shown to be activated transiently in response to physical stimuli such as physiological mechanical loading or hypo-osmotic stimuli.