An ASO therapy for Angelman syndrome that targets an evolutionarily conserved region at the start of the UBE3A-AS transcript.

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 paternal UBE3A allele is imprinted in neurons of the central nervous system (CNS) by the UBE3A antisense (UBE3A-AS) transcript, which represents the distal end of the small nucleolar host gene 14 (SNHG14) transcription unit. Reactivating the expression of the paternal UBE3A allele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we described the development of an antisense oligonucleotide (ASO) therapy for Angelman syndrome that targets an evolutionarily conserved region demarcating the start of the UBE3A-AS transcript. We designed and chemically optimized gapmer ASOs targeting specific sequences at the start of the human UBE3A-AS transcript. We showed that ASOs targeting this region precisely and efficiently repress the transcription of UBE3A-AS, reactivating the expression of the paternal UBE3A allele in neurotypical and Angelman syndrome induced pluripotent stem cell–derived neurons. We further showed that human-targeted ASOs administered to the CNS of cynomolgus macaques by lumbar intrathecal injection repress UBE3A-AS and reactivate the expression of the paternal UBE3A allele throughout the CNS. These findings support the advancement of this investigational molecular therapy for Angelman syndrome into clinical development (ClinicalTrials.gov, NCT04259281). ASOs for Angelman syndrome: Angelman syndrome is a neurodevelopmental disorder caused by mutations in the maternally inherited allele of the ubiquitin-protein ligase E3A (UBE3A) gene. In the central nervous system, the paternal allele of UBE3A is imprinted by the UBE3A antisense (UBE3A-AS) transcript, and reactivation of paternal UBE3A expression has been suggested as a potential treatment for the disease. Here, Dindot and colleagues developed antisense oligonucleotides (ASOs) that specifically target evolutionarily conserved sequences at the start of the UBE3A-AS transcript to repress UBE3A-AS transcription, leading to reactivation of the paternal UBE3A allele in vitro and in cynomolgus monkeys. Based on these findings, a clinical trial testing this ASO in patients with Angelman syndrome is underway. —MN [ABSTRACT FROM AUTHOR]