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Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

Author

Listed:
  • Kian Huat Lim

    (Stoke Therapeutics, Inc.)

  • Zhou Han

    (Stoke Therapeutics, Inc.)

  • Hyun Yong Jeon

    (Stoke Therapeutics, Inc.)

  • Jacob Kach

    (Stoke Therapeutics, Inc.)

  • Enxuan Jing

    (Stoke Therapeutics, Inc.)

  • Sebastien Weyn-Vanhentenryck

    (Stoke Therapeutics, Inc.)

  • Mikaela Downs

    (Stoke Therapeutics, Inc.)

  • Anna Corrionero

    (Stoke Therapeutics, Inc.)

  • Raymond Oh

    (Stoke Therapeutics, Inc.)

  • Juergen Scharner

    (Stoke Therapeutics, Inc.)

  • Aditya Venkatesh

    (Stoke Therapeutics, Inc.)

  • Sophina Ji

    (Stoke Therapeutics, Inc.)

  • Gene Liau

    (Stoke Therapeutics, Inc.)

  • Barry Ticho

    (Stoke Therapeutics, Inc.)

  • Huw Nash

    (Stoke Therapeutics, Inc.)

  • Isabel Aznarez

    (Stoke Therapeutics, Inc.)

Abstract

While most monogenic diseases are caused by loss or reduction of protein function, the need for technologies that can selectively increase levels of protein in native tissues remains. Here we demonstrate that antisense-mediated modulation of pre-mRNA splicing can increase endogenous expression of full-length protein by preventing naturally occurring non-productive alternative splicing and promoting generation of productive mRNA. Bioinformatics analysis of RNA sequencing data identifies non-productive splicing events in 7,757 protein-coding human genes, of which 1,246 are disease-associated. Antisense oligonucleotides targeting multiple types of non-productive splicing events lead to increases in productive mRNA and protein in a dose-dependent manner in vitro. Moreover, intracerebroventricular injection of two antisense oligonucleotides in wild-type mice leads to a dose-dependent increase in productive mRNA and protein in the brain. The targeting of natural non-productive alternative splicing to upregulate expression from wild-type or hypomorphic alleles provides a unique approach to treating genetic diseases.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17093-9
    DOI: 10.1038/s41467-020-17093-9
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    Cited by:

    1. Maritere Uriostegui-Arcos & Steven T. Mick & Zhuo Shi & Rufuto Rahman & Ana Fiszbein, 2023. "Splicing activates transcription from weak promoters upstream of alternative exons," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Hannah E. Salapa & Patricia A. Thibault & Cole D. Libner & Yulian Ding & Joseph-Patrick W. E. Clarke & Connor Denomy & Catherine Hutchinson & Hashim M. Abidullah & S. Austin Hammond & Landon Pastushok, 2024. "hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. 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.
    4. 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.

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