Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models.
Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models.
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DOI：
10.1038/s41467-021-21112-8
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发表时间：
2021-02-08
影响因子：
16.6
通讯作者：
Brown RH Jr
中科院分区：
文献类型：
--
作者：
Liu Y;Dodart JC;Tran H;Berkovitch S;Braun M;Byrne M;Durbin AF;Hu XS;Iwamoto N;Jang HG;Kandasamy P;Liu F;Longo K;Ruschel J;Shelke J;Yang H;Yin Y;Donner A;Zhong Z;Vargeese C;Brown RH Jr
C9orf72基因大的G4C2重复序列扩张是肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)最常见的遗传原因。与这种扩张相关的神经元变性是由于C9orf72蛋白的丢失、RNA焦点的聚集、二肽重复(DPR)蛋白的表达或所有这些因素引起的。我们报告发现了一个新的靶向序列，该序列对所有C9orf72转录本都是共同的，但在多个细胞模型和C9BAC转基因小鼠中能够优先敲除含有重复序列的转录本。我们优化了通过这个位点作用的立体视寡核苷酸，并证明了它们的优先活性取决于主干立体化学和不对称翅膀设计。在小鼠中，立体寡核苷酸在不干扰蛋白质表达的情况下产生致病特征的持久耗尽。这些寡核苷酸选择性地保护携带C9orf72扩展突变的运动神经元免受谷氨酸诱导的毒性。我们推测，靶向C9orf72的立体视觉寡核苷酸可能是治疗C9orf72相关神经退行性疾病的一种可行的治疗方法。C9ORF72扩展突变是ALS和FTD最常见的遗传原因，这两种疾病的治疗方法有限。作者产生立体寡核苷酸，在临床前模型中选择性地耗尽包含扩张的转录本，并保护其免受扩张相关病理的影响。
A large G4C2-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal degeneration associated with this expansion arises from a loss of C9orf72 protein, the accumulation of RNA foci, the expression of dipeptide repeat (DPR) proteins, or all these factors. We report the discovery of a new targeting sequence that is common to all C9orf72 transcripts but enables preferential knockdown of repeat-containing transcripts in multiple cellular models and C9BAC transgenic mice. We optimize stereopure oligonucleotides that act through this site, and we demonstrate that their preferential activity depends on both backbone stereochemistry and asymmetric wing design. In mice, stereopure oligonucleotides produce durable depletion of pathogenic signatures without disrupting protein expression. These oligonucleotides selectively protect motor neurons harboring C9orf72-expansion mutation from glutamate-induced toxicity. We hypothesize that targeting C9orf72 with stereopure oligonucleotides may be a viable therapeutic approach for the treatment of C9orf72-associated neurodegenerative disorders. C9orf72 expansion mutations are the most common genetic cause of ALS and FTD, which have limited therapies. The authors generate stereopure oligonucleotides that selectively deplete expansion-containing transcripts and protect against expansion-associated pathologies in preclinical models.
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影响因子：
16.2
作者：
Sopher BL;Ladd PD;Pineda VV;Libby RT;Sunkin SM;Hurley JB;Thienes CP;Gaasterland T;Filippova GN;La Spada AR
通讯作者：
La Spada AR
DOI：
10.1016/s1474-4422(12)70043-1
发表时间：
2012-04
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Majounie E;Renton AE;Mok K;Dopper EG;Waite A;Rollinson S;Chiò A;Restagno G;Nicolaou N;Simon-Sanchez J;van Swieten JC;Abramzon Y;Johnson JO;Sendtner M;Pamphlett R;Orrell RW;Mead S;Sidle KC;Houlden H;Rohrer JD;Morrison KE;Pall H;Talbot K;Ansorge O;Chromosome 9-ALS/FTD Consortium;French research network on FTLD/FTLD/ALS;ITALSGEN Consortium;Hernandez DG;Arepalli S;Sabatelli M;Mora G;Corbo M;Giannini F;Calvo A;Englund E;Borghero G;Floris GL;Remes AM;Laaksovirta H;McCluskey L;Trojanowski JQ;Van Deerlin VM;Schellenberg GD;Nalls MA;Drory VE;Lu CS;Yeh TH;Ishiura H;Takahashi Y;Tsuji S;Le Ber I;Brice A;Drepper C;Williams N;Kirby J;Shaw P;Hardy J;Tienari PJ;Heutink P;Morris HR;Pickering-Brown S;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
16.6
作者：
Du, Zhong-Wei;Chen, Hong;Liu, Huisheng;Lu, Jianfeng;Qian, Kun;Huang, CindyTzu-Ling;Zhong, Xiaofen;Fan, Frank;Zhang, Su-Chun
通讯作者：
Zhang, Su-Chun
DOI：
10.1126/science.1254917
发表时间：
2014-09-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kwon I;Xiang S;Kato M;Wu L;Theodoropoulos P;Wang T;Kim J;Yun J;Xie Y;McKnight SL
通讯作者：
McKnight SL
影响因子：
15.1
作者：
Ohki Y;Wenninger-Weinzierl A;Hruscha A;Asakawa K;Kawakami K;Haass C;Edbauer D;Schmid B
通讯作者：
Schmid B