Towards a therapy for Angelman syndrome by targeting a long non-coding RNA

摘要: Angelman syndrome is a single-gene disorder characterized by intellectual disability, developmental delay, behavioural uniqueness, speech impairment, seizures and ataxia. It caused maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase. All patients carry at least one copy paternal which intact but silenced nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS). Murine Ube3a-ATS reduction either transcription termination or topoisomerase I inhibition has been shown to increase Ube3a expression. Despite clear understanding disease-causing event in potential harness allele correct disease, no gene-specific treatment exists for patients. Here we developed therapeutic intervention reducing with oligonucleotides (ASOs). ASO achieved specific sustained unsilencing neurons vitro vivo. Partial restoration protein mouse model ameliorated some cognitive deficits associated disease. Although additional studies phenotypic correction are needed, have sequence-specific clinically feasible method activate expression allele.