Ube3a unsilencer for the potential treatment of Angelman syndrome

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 .