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

被引：115

作者：

d'Ydewalle, Constantin ^{[1
]}

Ramos, Daniel M. ^{[2
]}

Pyles, Noah J. ^{[1
]}

Ng, Shi-Yan ^{[3
,4
,7
]}

Gorz, Mariusz ^{[1
]}

Pilato, Celeste M. ^{[1
]}

Ling, Karen ^{[5
]}

Kong, Lingling ^{[1
]}

Ward, Amanda J. ^{[6
]}

Rubin, Lee L. ^{[3
,4
]}

Rigo, Frank ^{[5
]}

Bennett, C. Frank ^{[5
]}

Sumner, Charlotte J. ^{[1
,2
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Neurol, 855 North Wolfe St, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Neurosci, 855 North Wolfe St, Baltimore, MD 21205 USA

[3] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[4] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[5] Ionis Pharmaceut, 2855 Gazelle Court, Carlsbad, CA 92010 USA

[6] MIT, Koch Inst Integrat Canc Res, 500 Main St, Cambridge, MA 02142 USA

[7] Inst Mol & Cell Biol, Neurotherapeut Lab, 61 Biopolis Dr, Singapore 138673, Singapore

来源：

NEURON | 2017年 / 93卷 / 01期

关键词：

LONG NONCODING RNAS; X-CHROMOSOME INACTIVATION; H3; LYSINE-27; METHYLATION; MOUSE MODEL; NERVOUS-SYSTEM; NEURONAL DIFFERENTIATION; SINGLE NUCLEOTIDE; DETERMINING GENE; CARDIAC DEFECTS; STEM-CELLS;

D O I：

10.1016/j.neuron.2016.11.033

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：66 / 79

页数：14

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