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

• Published in: Nature (London) Vol. 518; no. 7539; pp. 409 - 412
• Main Authors: Meng, Linyan, Ward, Amanda J., Chun, Seung, Bennett, C. Frank, Beaudet, Arthur L., Rigo, Frank
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.02.2015; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/51; 14/32; 38/77; 38/90; 631/154; 631/208/366; 64/60; Alleles; Angelman Syndrome - complications; Angelman Syndrome - genetics; Angelman Syndrome - therapy; Animals; Binding sites; Brain - drug effects; Brain - metabolism; Cells, Cultured; Disease Models, Animal; DNA methylation; Fathers; Female; Gene Silencing - drug effects; Gene therapy; Genetic disorders; Genomic Imprinting - genetics; Health aspects; Humanities and Social Sciences; letter; Male; Memory Disorders - complications; Memory Disorders - genetics; Memory Disorders - therapy; Methods; Mice; Mice, Inbred C57BL; multidisciplinary; Neurons - drug effects; Neurons - metabolism; Obesity - complications; Obesity - genetics; Obesity - therapy; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - pharmacology; Oligonucleotides, Antisense - therapeutic use; Phenotype; Protein expression; Proteins; Ribonucleic acid; RNA; RNA, Antisense - antagonists & inhibitors; RNA, Antisense - deficiency; RNA, Antisense - genetics; RNA, Long Noncoding - antagonists & inhibitors; RNA, Long Noncoding - genetics; Rodents; Science; Time Factors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13975

Angelman syndrome is a neurodevelopmental disorder caused by disrupted function of the maternal copy of the imprinted UBE3A gene; here, targeting a long non-coding RNA that is responsible for silencing the paternal copy of UBE3A with antisense oligonucleotides is shown to partially restore UBE3A expression in the central nervous system and correct some cognitive deficits in a mouse model of the disease. Therapy for Angelman syndrome Frank Rigo and colleagues report the development of the first gene-specific therapy for Angelman syndrome, a severe neurodevelopmental disorder caused by disrupted function of the maternal copy of the imprinted gene UBE3A. The paternal copy of UBE3A is intact but silenced by a long non-coding RNA antisense transcript, UBE3A-ATS . The authors show that by reducing Ube3a-ATS with antisense oligonucleotides (ASOs), the silencing of paternal Ube3a can be reversed in cultured mouse neurons and in vivo . Some phenotypes in an Angelman syndrome mouse model, including obesity and memory impairment can also be corrected. Angelman syndrome is a single-gene disorder characterized by intellectual disability, developmental delay, behavioural 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 , 4 , 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 , 7 , 8 . Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition has been shown to increase paternal Ube3a expression 9 , 10 . Despite a clear understanding of the disease-causing event in Angelman syndrome and the potential to harness the intact paternal allele to correct the disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for Angelman syndrome 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 Angelman syndrome mouse model ameliorated some cognitive deficits associated with the disease. Although additional studies of phenotypic correction are needed, we have developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.