Ube3a unsilencer for the potential treatment of Angelman syndrome

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, Hyeong-Min Lee (), Jeffrey Aubé () and Benjamin D. Philpot ()
Additional contact information
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
Jeffrey Aubé: University of North Carolina at Chapel Hill
Benjamin D. Philpot: University of North Carolina at Chapel Hill

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-49788-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49788-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-49788-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().