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; Bryan C. Dickinson

doi:10.1038/s41467-023-42252-z

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, Bryan C. Dickinson^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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.

Original language	English (US)
Article number	6827
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-42252-z
State	Published - Dec 2023

Funding

This work was supported by the National Institute of General Medical Sciences (R35 GM119840), the National Institute of Mental Health (R01 MH122142, B.C.D.) of the National Institutes of Health (NIH), The G. Harold and Leila Y. Mathers Charitable Foundation (FP106237, B.C.D.), and the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (B.C.D. and S.T). We thank Ani Solanki from Animal Resource Center at University of Chicago for help with mouse experiments and Dr. Mark Berney for experimental assistance. We thank Dr. Somayeh Ahmadiantehrani, Tong Lan, and Riley Sinnott for assistance with drafts of the manuscript. Figures contain illustrations created with BioRender.com (Agreement number YO25UQKDCM) and were made with assistance from Dr. Somayeh Ahmadiantehrani. This work was supported by the National Institute of General Medical Sciences (R35 GM119840), the National Institute of Mental Health (R01 MH122142, B.C.D.) of the National Institutes of Health (NIH), The G. Harold and Leila Y. Mathers Charitable Foundation (FP106237, B.C.D.), and the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (B.C.D. and S.T). We thank Ani Solanki from Animal Resource Center at University of Chicago for help with mouse experiments and Dr. Mark Berney for experimental assistance. We thank Dr. Somayeh Ahmadiantehrani, Tong Lan, and Riley Sinnott for assistance with drafts of the manuscript. Figures contain illustrations created with BioRender.com (Agreement number YO25UQKDCM) and were made with assistance from Dr. Somayeh Ahmadiantehrani.

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1038/s41467-023-42252-z

Cite this

@article{642ac0197c9d49498b7b161f43843636,

title = "RNA-based translation activators for targeted gene upregulation",

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.",

author = "Yang Cao and Huachun Liu and Lu, {Shannon S.} and Jones, {Krysten A.} and Govind, {Anitha P.} and Okunola Jeyifous and Simmons, {Christine Q.} and Negar Tabatabaei and Green, {William N.} and Holder, {Jimmy L.} and Soroush Tahmasebi and George, {Alfred L.} and Dickinson, {Bryan C.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-42252-z",

language = "English (US)",

volume = "14",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - RNA-based translation activators for targeted gene upregulation

AU - Cao, Yang

AU - Liu, Huachun

AU - Lu, Shannon S.

AU - Jones, Krysten A.

AU - Govind, Anitha P.

AU - Jeyifous, Okunola

AU - Simmons, Christine Q.

AU - Tabatabaei, Negar

AU - Green, William N.

AU - Holder, Jimmy L.

AU - Tahmasebi, Soroush

AU - George, Alfred L.

AU - Dickinson, Bryan C.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85175083196&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85175083196&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-42252-z

DO - 10.1038/s41467-023-42252-z

M3 - Article

C2 - 37884512

AN - SCOPUS:85175083196

SN - 2041-1723

VL - 14

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 6827

ER -

RNA-based translation activators for targeted gene upregulation

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this