Development of an ASO therapy for Angelman syndrome by targeting an evolutionarily conserved region at the start of theUBE3A-AStranscript

Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A (UBE3A) gene. The paternalUBE3Aallele is imprinted in neurons of the central nervous system (CNS) by theUBE3Aantisense (UBE3A-AS) transcript, which represents the distal end of theSNHG14transcription unit. Reactivating the expression of the paternalUBE3Aallele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we designed and optimized antisense oligonucleotides (ASO) targeting an evolutionarily conserved region demarcating the start of the humanUBE3A-AStranscript and show that ASOs targeting this region can reverse imprinting ofUBE3Ain cultured Angelman syndrome neurons and throughout the CNS of a non-human primate model. Findings from this study advanced the first investigational molecular therapy for Angelman syndrome into clinical development (ClinicalTrials.gov,NCT04259281).SUMMARYHere, we describe the preclinical studies supporting the first investigational molecular therapy for Angelman syndrome to advance into clinical development (ClinicalTrials.gov,NCT04259281).