ERAD-level gene switches for on-demand protein secretion and rapidly controlled gene therapies.

On-demand regulation of therapeutic activities is critical to broaden the clinical utility of gene therapies. Here, we employ an Endoplasmic Reticulum-Associated Degradation (ERAD)-centered strategy to develop trigger-inducible gene switches tailor-designed for rapid protein secretion. By temporarily attaching conditional degron motifs to various therapeutic proteins of interest (POIs), inducible, tunable and reversible control of native POI secretion into the bloodstream was achieved through oral administration of specific clinically licensed small-molecule drugs. This simple and generalizable design principle is highly compatible with adeno-associated virus (AAV)-mediated gene delivery, enabling long-term and remote-controlled transgene expression in male mice in vivo. To showcase potential therapeutic benefits of ERAD-level gene switches, we describe gene therapy approaches for cardiovascular diseases and chronic pain - two classes of disease treatments that may most urgently require on-demand drug actions. This study achieves dose- and time-dependent control of transgene activities without requiring the design of overly complex gene circuits, and may form important basis to move synthetic biology-based regulation systems towards therapeutic usage.