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RNA-based translation activators for targeted gene upregulation

Author

Listed:
  • 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
    Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital)

  • Soroush Tahmasebi

    (University of Illinois College of Medicine)

  • Alfred L. George

    (Northwestern University Feinberg School of Medicine)

  • Bryan C. Dickinson

    (The University of Chicago)

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.

Suggested Citation

  • 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 & Al, 2023. "RNA-based translation activators for targeted gene upregulation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42252-z
    DOI: 10.1038/s41467-023-42252-z
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    References listed on IDEAS

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    1. Yaser Hashem & Amedee des Georges & Vidya Dhote & Robert Langlois & Hstau Y. Liao & Robert A. Grassucci & Tatyana V. Pestova & Christopher U. T. Hellen & Joachim Frank, 2013. "Hepatitis-C-virus-like internal ribosome entry sites displace eIF3 to gain access to the 40S subunit," Nature, Nature, vol. 503(7477), pages 539-543, November.
    2. Jennine M. Dawicki-McKenna & Alex J. Felix & Elisa A. Waxman & Congsheng Cheng & Defne A. Amado & Paul T. Ranum & Alexey Bogush & Lea V. Dungan & Jean Ann Maguire & Alyssa L. Gagne & Elizabeth A. Hell, 2023. "Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Kian Huat Lim & Zhou Han & Hyun Yong Jeon & Jacob Kach & Enxuan Jing & Sebastien Weyn-Vanhentenryck & Mikaela Downs & Anna Corrionero & Raymond Oh & Juergen Scharner & Aditya Venkatesh & Sophina Ji & , 2020. "Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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