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Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA

Author

Listed:
  • Justin M. Wolter

    (The University of North Carolina at Chapel Hill
    The University of North Carolina at Chapel Hill
    The University of North Carolina at Chapel Hill)

  • Hanqian Mao

    (The University of North Carolina at Chapel Hill
    The University of North Carolina at Chapel Hill
    The University of North Carolina at Chapel Hill)

  • Giulia Fragola

    (The University of North Carolina at Chapel Hill)

  • Jeremy M. Simon

    (The University of North Carolina at Chapel Hill
    The University of North Carolina at Chapel Hill
    The University of North Carolina at Chapel Hill)

  • James L. Krantz

    (The University of North Carolina at Chapel Hill)

  • Hannah O. Bazick

    (The University of North Carolina at Chapel Hill)

  • Baris Oztemiz

    (The University of North Carolina at Chapel Hill)

  • Jason L. Stein

    (The University of North Carolina at Chapel Hill
    The University of North Carolina at Chapel Hill)

  • Mark J. Zylka

    (The University of North Carolina at Chapel Hill
    The University of North Carolina at Chapel Hill
    The University of North Carolina at Chapel Hill)

Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a mutation or deletion of the maternally inherited UBE3A allele. In neurons, the paternally inherited UBE3A allele is silenced in cis by a long non-coding RNA called UBE3A-ATS. Here, as part of a systematic screen, we found that Cas9 can be used to activate ('unsilence') paternal Ube3a in cultured mouse and human neurons when targeted to Snord115 genes, which are small nucleolar RNAs that are clustered in the 3′ region of Ube3a-ATS. A short Cas9 variant and guide RNA that target about 75 Snord115 genes were packaged into an adeno-associated virus and administered to a mouse model of AS during the embryonic and early postnatal stages, when the therapeutic benefit of restoring Ube3a is predicted to be greatest1,2. This early treatment unsilenced paternal Ube3a throughout the brain for at least 17 months and rescued anatomical and behavioural phenotypes in AS mice. Genomic integration of the adeno-associated virus vector into Cas9 target sites caused premature termination of Ube3a-ATS at the vector-derived polyA cassette, or when integrated in the reverse orientation, by transcriptional collision with the vector-derived Cas9 transcript. Our study shows that targeted genomic integration of a gene therapy vector can restore the function of paternally inherited UBE3A throughout life, providing a path towards a disease-modifying treatment for a syndromic neurodevelopmental disorder.

Suggested Citation

  • Justin M. Wolter & Hanqian Mao & Giulia Fragola & Jeremy M. Simon & James L. Krantz & Hannah O. Bazick & Baris Oztemiz & Jason L. Stein & Mark J. Zylka, 2020. "Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA," Nature, Nature, vol. 587(7833), pages 281-284, November.
  • Handle: RePEc:nat:nature:v:587:y:2020:i:7833:d:10.1038_s41586-020-2835-2
    DOI: 10.1038/s41586-020-2835-2
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    Cited by:

    1. Hanna Vihma & Kelin Li & Anna Welton-Arndt & Audrey L. Smith & Kiran R. Bettadapur & Rachel B. Gilmore & Eric Gao & Justin L. Cotney & Hsueh-Cheng Huang & Jon L. Collins & Stormy J. Chamberlain & Hyeo, 2024. "Ube3a unsilencer for the potential treatment of Angelman syndrome," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Jifeng Yu & Bangguo Zhou & Shen Zhang & Haohao Yin & Liping Sun & Yinying Pu & Boyang Zhou & Yikang Sun & Xiaolong Li & Yan Fang & Lifan Wang & Chongke Zhao & Dou Du & Yan Zhang & Huixiong Xu, 2022. "Design of a self-driven probiotic-CRISPR/Cas9 nanosystem for sono-immunometabolic cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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