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Ube3a unsilencer for the potential treatment of Angelman syndrome

Author

Listed:
  • Hanna Vihma

    (University of North Carolina at Chapel Hill)

  • Kelin Li

    (University of North Carolina at Chapel Hill)

  • Anna Welton-Arndt

    (University of North Carolina at Chapel Hill)

  • Audrey L. Smith

    (University of North Carolina at Chapel Hill)

  • Kiran R. Bettadapur

    (University of North Carolina at Chapel Hill)

  • Rachel B. Gilmore

    (University of Connecticut School of Medicine)

  • Eric Gao

    (University of North Carolina at Chapel Hill)

  • Justin L. Cotney

    (University of Connecticut School of Medicine)

  • Hsueh-Cheng Huang

    (Deerfield Management)

  • Jon L. Collins

    (University of North Carolina at Chapel Hill)

  • Stormy J. Chamberlain

    (University of Connecticut School of Medicine)

  • Hyeong-Min Lee

    (University of North Carolina at Chapel Hill
    Hollings Cancer Center, Medical University of South Carolina)

  • Jeffrey Aubé

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

  • Benjamin D. Philpot

    (University of North Carolina at Chapel Hill)

Abstract

Deletion of the maternal UBE3A allele causes Angelman syndrome (AS); because paternal UBE3A is epigenetically silenced by a long non-coding antisense (UBE3A-ATS) in neurons, this nearly eliminates UBE3A protein in the brain. Reactivating paternal UBE3A holds promise for treating AS. We previously showed topoisomerase inhibitors can reactivate paternal UBE3A, but their therapeutic challenges prompted our search for small molecule unsilencers with a different mechanism of action. Here, we found that (S)-PHA533533 acts through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice. Furthermore, peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression. Finally, we show that (S)-PHA533533 unsilences paternal UBE3A in AS patient-derived neurons, highlighting its translational potential. Our findings provide a lead for developing a small molecule treatment for AS that could be safe, non-invasively delivered, and capable of brain-wide unsilencing of paternal UBE3A.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49788-8
    DOI: 10.1038/s41467-024-49788-8
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    References listed on IDEAS

    as
    1. 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.
    2. Ian F. King & Chandri N. Yandava & Angela M. Mabb & Jack S. Hsiao & Hsien-Sung Huang & Brandon L. Pearson & J. Mauro Calabrese & Joshua Starmer & Joel S. Parker & Terry Magnuson & Stormy J. Chamberlai, 2013. "Topoisomerases facilitate transcription of long genes linked to autism," Nature, Nature, vol. 501(7465), pages 58-62, September.
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