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The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy.
- Source :
-
Neuron [Neuron] 2017 Jan 04; Vol. 93 (1), pp. 66-79. Date of Electronic Publication: 2016 Dec 22. - Publication 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.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Blotting, Western
Cells, Cultured
Cerebral Cortex cytology
Chromatin Immunoprecipitation
Disease Models, Animal
Humans
Induced Pluripotent Stem Cells
Mice
Muscular Atrophy, Spinal metabolism
Neurons metabolism
Oligonucleotides, Antisense pharmacology
Polycomb Repressive Complex 2 metabolism
Promoter Regions, Genetic
RNA Splicing
RNA, Antisense drug effects
RNA, Antisense metabolism
RNA, Long Noncoding drug effects
RNA, Long Noncoding metabolism
Real-Time Polymerase Chain Reaction
Survival of Motor Neuron 1 Protein metabolism
Survival of Motor Neuron 2 Protein metabolism
Gene Expression Regulation
Motor Neurons metabolism
Muscular Atrophy, Spinal genetics
RNA, Antisense genetics
RNA, Long Noncoding genetics
Survival of Motor Neuron 1 Protein genetics
Survival of Motor Neuron 2 Protein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4199
- Volume :
- 93
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Neuron
- Publication Type :
- Academic Journal
- Accession number :
- 28017471
- Full Text :
- https://doi.org/10.1016/j.neuron.2016.11.033