RNA-based translation activators for targeted gene upregulation

Yang Cao, Huachun Liu, Shannon S. Lu, Krysten A. Jones, Anitha P. Govind, Okunola Jeyifous, Christine Q. Simmons, Negar Tabatabaei, William N. Green, Jimmy. L. Holder, Soroush Tahmasebi, Alfred L. George and Bryan C. Dickinson ()
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Yang Cao: The University of Chicago
Huachun Liu: The University of Chicago
Shannon S. Lu: The University of Chicago
Krysten A. Jones: The University of Chicago
Anitha P. Govind: The University of Chicago
Okunola Jeyifous: The University of Chicago
Christine Q. Simmons: Northwestern University Feinberg School of Medicine
Negar Tabatabaei: University of Illinois College of Medicine
William N. Green: The University of Chicago
Jimmy. L. Holder: Baylor College of Medicine
Soroush Tahmasebi: University of Illinois College of Medicine
Alfred L. George: Northwestern University Feinberg School of Medicine
Bryan C. Dickinson: The University of Chicago

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42252-z

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