The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy.
The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy.
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DOI：
10.1016/j.neuron.2016.11.033
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发表时间：
2017-01-04
期刊：
影响因子：
16.2
通讯作者：
Sumner CJ
中科院分区：
文献类型：
--
作者：
d'Ydewalle C;Ramos DM;Pyles NJ;Ng SY;Gorz M;Pilato CM;Ling K;Kong L;Ward AJ;Rubin LL;Rigo F;Bennett CF;Sumner CJ
神经肌肉疾病脊髓性肌萎缩症（SMA）是婴儿最常见的遗传杀手，是由运动神经元存活蛋白（SMN）表达不足引起的。 SMA 疗法开发工作的重点是确定增加 SMN 表达的策略。我们鉴定了一种源自 SMN 反义链 SMN-AS1 的长非编码 RNA (lncRNA)，它在神经元中富集，并通过招募表观遗传 Polycomb 抑制复合物 2 来转录抑制 SMN 表达。用反义寡核苷酸 (ASO) 靶向降解 SMN-AS1 可增加患者来源的细胞、培养的神经元和小鼠中枢神经系统中的 SMN 表达。 SMN-AS1 ASO 与 SMN2 剪接转换寡核苷酸一起递送可额外增加 SMN 表达并提高严重 SMA 小鼠的存活率。这项研究首次证明了靶向 lncRNA 转录激活 SMN2 可以与 SMN2 剪接修饰相结合以改善 SMA，并展示了组合 ASO 治疗神经遗传性疾病的前景。 eTOC 简介 d’Ydewalle 等人。鉴定出一种 lncRNA，该 lncRNA 在神经元中以 PRC2 依赖性方式调节 SMN2 表达。靶向 SMN-AS1 与 SMN2 剪接修饰剂组合对 SMN 表达具有累加效应，并改善严重 SMA 小鼠的表型。
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 treatment of neurogenetic disorders. eTOC blurb d’Ydewalle et al. identify a lncRNA that regulates SMN2 expression in a PRC2-dependent manner in neurons. Targeting SMN-AS1 in combination with SMN2 splicing modifiers has additive effects on SMN expression and improves the phenotype of severe SMA mice.