NDLI: The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy

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The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy

Content Provider	Semantic Scholar
Author	Ydewalle, Constantin D’ Ramos, Daniel Pyles, Noah Ng, Shi-Yan Gorz, Mariusz Pilato, C. Michael Ling, Karen K. Y. Kong, Lingling Ward, Amanda Jane Rubin, Lee L. Rigo, Frank Bennett, C. Frank Sumner, Charlotte J.
Copyright Year	2017
Abstract	The neuromuscular disorder spinal muscular atrophy (SMA), the most common inherited killer of infants, is caused by insufficient expression of survival motor neuron (SMN) protein. SMA therapeutics development efforts have focused on identifying strategies to increase SMN expression. We identified a long non-coding RNA (lncRNA) that arises from the antisense strand of SMN, SMN-AS1, which is enriched in neurons and transcriptionally represses SMN expression by recruiting the epigenetic Polycomb repressive complex-2. Targeted degradation of SMN-AS1 with antisense oligonucleotides (ASOs) increases SMN expression in patient-derived cells, cultured neurons, and the mouse central nervous system. SMN-AS1 ASOs delivered together with SMN2 splice-switching oligonucleotides additively increase SMN expression and improve survival of severe SMA mice. This study is the first proof of concept that targeting a lncRNA to transcriptionally activate SMN2 can be combined with SMN2 splicing modification to ameliorate SMA and demonstrates the promise of combinatorial ASOs for the treatment of neurogenetic disorders.
Starting Page	66
Ending Page	79
Page Count	14
File Format	PDF HTM / HTML
DOI	10.1016/j.neuron.2016.11.033
PubMed reference number	28017471
Journal	Medline
Volume Number	93
Alternate Webpage(s)	https://api.elsevier.com/content/article/pii/S0896627316309011
Alternate Webpage(s)	https://www.sciencedirect.com/science/article/pii/S0896627316309011
Alternate Webpage(s)	https://doi.org/10.1016/j.neuron.2016.11.033
Journal	Neuron
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article

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The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy