Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis.
Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis.
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反义寡核苷酸沉默将FUS表达作为肌萎缩性侧索硬化症的治疗方法。
DOI：
10.1038/s41591-021-01615-z
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发表时间：
2022-01
期刊：
影响因子：
82.9
通讯作者：
Shneider NA
中科院分区：
文献类型：
--
作者：
Korobeynikov VA;Lyashchenko AK;Blanco-Redondo B;Jafar-Nejad P;Shneider NA
融合肉瘤（FUS）是一种rna结合蛋白，在遗传和病理上与罕见的侵袭性肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）相关。为了探索突变FUS导致ALS-FTD神经退行性变的机制，我们产生了一系列表达als相关突变FUSP525L和FUSΔEX14蛋白的FUS敲入小鼠系。在FUS突变小鼠中，我们发现，由于毒性功能的剂量依赖性增加，与FUS和相关rna结合蛋白的不溶性相关，进行性的、年龄依赖性的运动神经元丧失。在这种疾病相关的ALS-FUS小鼠模型中，我们发现ION363，一种非等位基因特异性的FUS反义寡核苷酸，有效地沉默FUS并降低出生后脑和脊髓中FUS蛋白的水平，延缓运动神经元的变性。在一名患有FUSP525L突变的ALS患者中，我们提供了初步证据，反复鞘内输注ION363可降低中枢神经系统中野生型和突变型FUS水平，从而显著减少FUS聚集物的负担，而FUS聚集物是疾病的病理标志。在小鼠遗传和人类临床研究中，我们提供证据支持FUS沉默作为FUS依赖性ALS和FTD的治疗策略。一种针对rna结合蛋白FUS转录物的反义寡核苷酸降低了小鼠和单个FUS依赖性ALS患者中枢神经系统中的FUS水平
Fused in sarcoma (FUS) is an RNA-binding protein that is genetically and pathologically associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To explore the mechanisms by which mutant FUS causes neurodegeneration in ALS-FTD, we generated a series of FUS knock-in mouse lines that express the equivalent of ALS-associated mutant FUSP525L and FUSΔEX14 protein. In FUS mutant mice, we show progressive, age-dependent motor neuron loss as a consequence of a dose-dependent gain of toxic function, associated with the insolubility of FUS and related RNA-binding proteins. In this disease-relevant mouse model of ALS-FUS, we show that ION363, a non-allele-specific FUS antisense oligonucleotide, efficiently silences Fus and reduces postnatal levels of FUS protein in the brain and spinal cord, delaying motor neuron degeneration. In a patient with ALS with a FUSP525L mutation, we provide preliminary evidence that repeated intrathecal infusions of ION363 lower wild-type and mutant FUS levels in the central nervous system, resulting in a marked reduction in the burden of FUS aggregates that are a pathological hallmark of disease. In mouse genetic and human clinical studies, we provide evidence in support of FUS silencing as a therapeutic strategy in FUS-dependent ALS and FTD. An antisense oligonucleotide targeting the RNA-binding protein FUS transcript lowers FUS levels in mice and in the central nervous system of a single patient with FUS-dependent ALS
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影响因子：
16.6
作者：
Sharma A;Lyashchenko AK;Lu L;Nasrabady SE;Elmaleh M;Mendelsohn M;Nemes A;Tapia JC;Mentis GZ;Shneider NA
通讯作者：
Shneider NA
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
4.4
作者：
Cedarbaum, JM;Stambler, N;Nakanishi, A
通讯作者：
Nakanishi, A
影响因子：
25
作者：
Pun, S;Santos, AF;Caroni, P
通讯作者：
Caroni, P
影响因子：
4.8
作者：
Kim, Sang Hwa;Shanware, Naval P.;Tibbetts, Randal S.
通讯作者：
Tibbetts, Randal S.