Published October 26, 2023
| Version v1
Journal article
Open
RNA-based translation activators for targeted gene upregulation
Creators
- 1. University of Chicago
- 2. Northwestern University
- 3. University of Illinois College
- 4. Baylor College of Medicine
- 5. University of Illinois Chicago
Description
Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present "translation-activating RNAs" (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs. We minimize the taRNA scaffold to 94 nucleotides, identify two translation initiation factor proteins responsible for taRNA activity, and validate the technology by amplifying SYNGAP1 expression, a haploinsufficiency disease target, in patient-derived cells. Finally, taRNAs are suitable for delivery as RNA molecules by lipid nanoparticles (LNPs) to cell lines, primary neurons, and mouse liver in vivo. taRNAs provide a general and compact nucleic acid-based technology to upregulate protein production from endogenous mRNAs, and may open up possibilities for therapeutic RNA research.
Data availability
Source data are provided with this paper.Files
RNA-based-translation-activators-for-targeted-gene-upregulation.pdf
Additional details
Identifiers
- DOI
- 10.1038/s41467-023-42252-z
- Other
- oai:uchicago.tind.io:9366
Funding
- National Institute of General Medical Sciences
- R35 GM119840
- National Institute of Mental Health
- R01 MH122142
- G. Harold and Leila Y. Mathers Charitable Foundation
- FP106237
- The Chicago Community Trust
- Searle Funds