Journal Article

Ube3a unsilencer for the potential treatment of Angelman syndrome

Chamberlain, Stormy J., Welton-Arndt, Anna, Smith, Audrey L., Bettadapur, Kiran R., Gao, Eric, Aubé, Jeffrey, Li, Kelin, Lee, Hyeong-Min, Philpot, Benjamin D., Gilmore, Rachel B., Huang, Hsueh-Cheng, Collins, Jon L., Vihma, Hanna, Cotney, Justin L.

2024

Overview

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 . Angelman syndrome is a neurodevelopmental disorder caused by the deletion of a single gene. Here, researchers discovered a small molecule that could be delivered peripherally to activate a dormant copy of the gene throughout the brain, providing a potential treatment opportunity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/100 / 13/106 / 13/51 / 13/89 / 14/63 / 49/98 / 631/378/1689/1373 / 631/378/2571 / 64/110 / 64/60 / Angelman Syndrome - genetics / Angelman's syndrome / Animal models / Animals / Biology / Brain / Brain - metabolism / CRISPR / Cyclin-dependent kinases / Deletion / Disease Models, Animal / Female / Gene deletion / Humanities and Social Sciences / Humans / Kinases / Male / Mice / mRNA / multidisciplinary / Mutation / Neurodevelopmental disorders / Neurons / Neurons - metabolism / Proteins / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / Therapeutic applications / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism