Splice-switching antisense oligonucleotides as therapeutic drugs.
Splice-switching antisense oligonucleotides as therapeutic drugs.
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DOI：
10.1093/nar/gkw533
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发表时间：
2016-08-19
影响因子：
14.9
通讯作者：
Hastings ML
中科院分区：
文献类型：
--
作者：
Havens MA;Hastings ML
剪接开关寡核苷酸（Splice-switching oligonucleotides, SSOs）是一种短的、合成的、反义的、修饰的核酸，其碱基与前体mrna配对，并通过阻断剪接机制的组成部分与前体mrna之间发生的RNA-RNA碱基配对或蛋白质- rna结合相互作用，破坏转录本的正常剪接库。pre-mRNA的剪接是绝大多数蛋白质编码基因正确表达所必需的，因此，靶向这一过程提供了一种操纵基因产生蛋白质的方法。在由导致正常剪接中断的突变引起的疾病或当干扰基因转录物的正常剪接过程可能具有治疗作用时，剪接调节特别有价值。sso提供了一种有效和特定的方法来靶向和改变剪接的治疗方式。在这里，我们讨论了使用sso靶向和改变前mrna剪接的不同方法。我们详细介绍了核酸的修饰，使它们成为有希望的治疗方法，并讨论了创造有效的SSO药物的挑战。我们重点介绍了用于治疗杜氏肌营养不良症和脊髓性肌萎缩症的sso的发展，目前正在临床试验中进行测试。
Splice-switching oligonucleotides (SSOs) are short, synthetic, antisense, modified nucleic acids that base-pair with a pre-mRNA and disrupt the normal splicing repertoire of the transcript by blocking the RNA–RNA base-pairing or protein–RNA binding interactions that occur between components of the splicing machinery and the pre-mRNA. Splicing of pre-mRNA is required for the proper expression of the vast majority of protein-coding genes, and thus, targeting the process offers a means to manipulate protein production from a gene. Splicing modulation is particularly valuable in cases of disease caused by mutations that lead to disruption of normal splicing or when interfering with the normal splicing process of a gene transcript may be therapeutic. SSOs offer an effective and specific way to target and alter splicing in a therapeutic manner. Here, we discuss the different approaches used to target and alter pre-mRNA splicing with SSOs. We detail the modifications to the nucleic acids that make them promising therapeutics and discuss the challenges to creating effective SSO drugs. We highlight the development of SSOs designed to treat Duchenne muscular dystrophy and spinal muscular atrophy, which are currently being tested in clinical trials.
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DOI：
10.1038/mtna.2012.30
发表时间：
2012-08-14
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1038/mt.2012.264
发表时间：
2013-03
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
影响因子：
168.9
作者：
Cirak, Sebahattin;Arechavala-Gomeza, Virginia;Guglieri, Michela;Feng, Lucy;Torelli, Silvia;Anthony, Karen;Abbs, Stephen;Garralda, Maria Elena;Bourke, John;Wells, Dominic J.;Dickson, George;Wood, Matthew J. A.;Wilton, Steve D.;Straub, Volker;Kole, Ryszard;Shrewsbury, Stephen B.;Sewry, Caroline;Morgan, Jennifer E.;Bushby, Kate;Muntoni, Francesco
通讯作者：
Muntoni, Francesco
影响因子：
82.9
作者：
Alter, J;Lou, F;Lu, QL
通讯作者：
Lu, QL
影响因子：
30.8
作者：
Cartegni, L;Krainer, AR
通讯作者：
Krainer, AR