DESNASEs: a group of RNASE-based safety switches for Controlled Cell Elimination

Safety switch systems represent gene expression units capable of transcription and translation, resulting in the production of polypeptides that induce cell death upon exposure to specific activating ligands. This discourse introduces RNAse-based safety switches, collectively known as DESNase (a combination of the words ‘destabilized’ and ‘RNAse’), capable of activation through small molecule ligands such as Shield-1, Trimethoprim, Methotrexate, or 4-hydroxytamoxifen. The DESNase system comprises a fusion of a cytotoxic domain (an RNAse polypeptide) and a destabilizing domain. The latter prompts rapid degradation of the entire fusion polypeptide. In the presence of a small molecule ligand, also referred to as a trigger or activator, the DESNAse is stabilized, enabling the cytotoxic domain to initiate the degradation of its RNA substrates. This action block protein synthesis, ultimately culminating in cell death.