Journal
NATURE CHEMICAL BIOLOGY
Volume 14, Issue 11, Pages 1043-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-018-0146-9
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Funding
- Defense Advanced Research Projects Agency [W911NF-11-2-0054, W32P4Q-13-1-0011]
- National Science Foundation (NSF) [1522074, 1521759, CCF-1521925, CNS- 1446607, MCB-1745645]
- National Institutes of Health [5-R01-CA206218]
- Ragon Institute of MGH, MIT and Harvard
- Ghent University
- Research Foundation - Flanders (FWO) [G.0235.11N, G.0621.10N]
- Crucell Holland B.V.
- MIT-Amgen UROP Scholars Program
- Gabilan Stanford Graduate Fellowship
- Fannie and John Hertz Foundation Fellowship
- Stanford EDGE-STEM Doctoral Fellowship
- FWO
- Emmanuel van der Schueren fellowship from Kom op tegen Kanker
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Synthetic mRNA is an attractive vehicle for gene therapies because of its transient nature and improved safety profile over DNA. However, unlike DNA, broadly applicable methods to control expression from mRNA are lacking. Here we describe a platform for small-molecule-based regulation of expression from modified RNA (modRNA) and self-replicating RNA (replicon) delivered to mammalian cells. Specifically, we engineer small-molecule-responsive RNA binding proteins to control expression of proteins from RNA-encoded genetic circuits. Coupled with specific modRNA dosages or engineered elements from a replicon, including a subgenomic promoter library, we demonstrate the capability to externally regulate the timing and level of protein expression. These control mechanisms facilitate the construction of ON, OFF, and two-output switches, with potential therapeutic applications such as inducible cancer immunotherapies. These circuits, along with other synthetic networks that can be developed using these tools, will expand the utility of synthetic mRNA as a therapeutic modality.
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