2. Academic Validation
  3. Ube3a unsilencer for the potential treatment of Angelman syndrome

Ube3a unsilencer for the potential treatment of Angelman syndrome

  • Nat Commun. 2024 Jul 8;15(1):5558. doi: 10.1038/s41467-024-49788-8.
Hanna Vihma 1,  Kelin Li # 2,  Anna Welton-Arndt # 3,  Audrey L Smith 1,  Kiran R Bettadapur 1,  Rachel B Gilmore 4,  Eric Gao 1,  Justin L Cotney 4,  Hsueh-Cheng Huang 5,  Jon L Collins 6,  Stormy J Chamberlain 4,  Hyeong-Min Lee 7 8,  Jeffrey Aubé 9 10,  Benjamin D Philpot 11
Affiliations

Affiliations

  • 1 Department of Cell Biology and Physiology, Neuroscience Center, and Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 2 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 3 Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 4 Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA.
  • 5 Deerfield Discovery and Development, Deerfield Management, New York, NY, USA.
  • 6 Office of the Vice Chancellor for Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 7 Department of Cell Biology and Physiology, Neuroscience Center, and Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. dr.hmlee@gmail.com.
  • 8 Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA. dr.hmlee@gmail.com.
  • 9 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jaube@email.unc.edu.
  • 10 Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jaube@email.unc.edu.
  • 11 Department of Cell Biology and Physiology, Neuroscience Center, and Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. bphilpot@med.unc.edu.
  • # Contributed equally.
PMID: 38977672 DOI: 10.1038/s41467-024-49788-8
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.

Figures
Products