SNORD115 region of the UBE3A antisense transcript (SNORD115/UBE3A-ATS)

The SNORD115 region of the UBE3A antisense transcript (UBE3A-ATS) is a critical regulatory element within the 15q11.2-q13.3 chromosomal region. In neurons, the UBE3A-ATS is expressed exclusively from the paternal allele and extends through the UBE3A gene in the antisense direction, silencing paternal UBE3A expression through transcriptional interference [PMID: 22193661]. Angelman syndrome occurs when the maternal UBE3A allele is mutated or deleted, leaving the brain devoid of functional UBE3A protein. Therapeutic strategies target the SNORD115 region of the UBE3A-ATS using antisense oligonucleotides (ASOs) to trigger RNase H-mediated degradation of the transcript [PMID: 25470039]. By removing this antisense interference, the paternal UBE3A allele can be "unsilenced," restoring UBE3A protein levels in neurons. This approach is currently being evaluated in clinical trials with candidates such as GTX-102 and Rugonersen as a potential disease-modifying treatment for Angelman syndrome [NCT04259282, NCT04428281]. Beyond Angelman syndrome, the SNORD115 region is also implicated in Prader-Willi syndrome, where its deletion contributes to the disease phenotype. Successful modulation of this target requires precise delivery to the central nervous system, typically via intrathecal injection. Monitoring of this target involves assessing UBE3A protein levels and neurophysiological changes such as EEG delta power. Safety considerations include potential inflammatory responses to the ASOs and the impact of depleting the SNORD115 snoRNAs themselves.

Other names

SNHG14HBII-52UBE3A-ASSNORD115 cluster

Antisense oligonucleotide-mediated RNase H-dependent degradation of the UBE3A-ATS transcript to restore expression of the paternal UBE3A allele [PMID: 25470039].