ABSTRACT
mRNA drugs can encode any protein and are regarded as a promising therapeutic modality. However, current mRNA drugs are not designed to enable conditional translation, although disease states and appropriate therapeutic protein levels can fluctuate. As extracellular biomolecules can serve as disease markers, in this study, we developed an extracellular ligand-responsive translational regulation system. This system consists of a tobacco etch virus protease (TEVp)-fused receptor and TEVp-sensitive translational regulator, which releases target mRNAs upon detecting disease markers such as arginine vasopressin, prostaglandin E2, and bradykinin. Furthermore, both translational upregulation and downregulation were achieved by changing the design of the target mRNA. Finally, we succeeded in suppressing the inflammatory signal through the translational upregulation of an anti-inflammatory protein. This system will pave the way for the next generation of mRNA therapy that enables disease state-matched production of therapeutic proteins.
Competing Interest Statement
Tokyo Medical and Dental University has applied for a patent regarding the extracellular ligand-responsive translational regulation system.
Footnotes
The figure numbers on page 12 were incorrect, so we have corrected them. In addition, we amended the DDBJ accession number in materials and methods and data availability sections.
