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

Angelman syndrome (AS) is a single gene disorder characterized by intellectual disability, developmental delay, behavioral uniqueness, speech impairment, seizures, and ataxia(1,2). It is caused by maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase(3-5). All patients carry at least one copy of paternal UBE3A, which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS)(6-8). Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition increased paternal Ube3a expression(9,10). Despite a clear understanding of the disease-causing event in AS and the potential to harness the intact paternal allele to correct disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for AS by reducing Ube3a-ATS with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3a-ATS and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo. Partial restoration of UBE3A protein in an AS mouse model ameliorated some cognitive deficits associated with the disease. Although additional studies of phenotypic correction are needed, for the first time we developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.