RNA-based Translation Activators for Targeted Gene Upregulation

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Oct 26

PMID 37884512

Authors

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 Jr

Soroush Tahmasebi

Alfred L George Jr

Bryan C Dickinson

Affiliations

Soon will be listed here.

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.

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