Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome.
Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome.
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DOI：
10.1016/j.ebiom.2016.05.011
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发表时间：
2016-07
期刊：
影响因子：
11.1
通讯作者：
Wahlestedt C
中科院分区：
文献类型：
--
作者：
Hsiao J;Yuan TY;Tsai MS;Lu CY;Lin YC;Lee ML;Lin SW;Chang FC;Liu Pimentel H;Olive C;Coito C;Shen G;Young M;Thorne T;Lawrence M;Magistri M;Faghihi MA;Khorkova O;Wahlestedt C
Dravet综合征是由电压门控钠通道基因SCN 1A的杂合性功能丧失突变引起的破坏性遗传性脑疾病。目前没有治疗方法，但SCN 1A健康等位基因的上调代表了一种有吸引力的治疗策略。在这项研究中，我们确定了一种新的，进化保守的机制控制的表达SCN 1A，是由一个反义非编码RNA（SCN 1ANAT）介导的。使用靶向SCN1ANAT的基于阿替尼肽的化合物（AntagoNAT），我们能够在Dravet敲入小鼠模型和非人灵长类动物的脑中在体外和体内诱导SCN1A的特异性上调。在出生后Dravet小鼠中，AntagoNAT介导的Scn1a上调导致癫痫发作表型和海马中间神经元兴奋性的显着改善。这些结果进一步阐明了Dravet综合征的病理生理学，并概述了一种可能的新方法，用于治疗这种和其他具有类似病因的遗传性疾病。Dravet综合征基因SCN1A的表达可以使用靶向调节性ncRNA的基于阿托伐他汀的化合物（AntagoNAT）在猴和Dravet小鼠体内增加AntagoNAT治疗导致SCN1A上调和疾病表型的显著改善这些结果概述了治疗Dravet综合征和具有类似病因的其他疾病的可能的新方法。
Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology. Expression of the Dravet syndrome gene SCN1A can be increased using oligonucleotide-based compounds (AntagoNATs) targeting a regulatory ncRNA AntagoNAT treatment in vivo in monkeys and Dravet mice led to SCN1A upregulation and significant improvements in disease phenotype These results outline a possible new approach for the treatment of Dravet syndrome and other disorders with similar etiology