小柯机器人

美国哥伦比亚大学Neil A. Shneider研究小组发现，反义寡核苷酸沉默FUS表达可作为肌萎缩侧索硬化症的治疗方法。该研究于2022年1月24日在线发表于国际一流学术期刊《自然—医学》。

为了探索突变体Fused in sarcoma（FUS）导致肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）神经变性的机制，研究人员产生了一系列FUS基因敲入小鼠品系，这些品系表达相当于ALS相关的突变体FUSP525L和FUSΔEX14蛋白。在FUS突变体小鼠中，研究人员发现渐进的、年龄依赖性的运动神经元损失，这是毒性功能剂量依赖性增加的结果，与FUS和相关RNA结合蛋白的不可溶性有关。

在这种与疾病相关的ALS-FUS小鼠模型中，研究人员发现ION363（一种非等位特异性的FUS反义寡核苷酸）能有效地沉默Fus并降低大脑和脊髓中FUS蛋白的产后水平，并延缓运动神经元的退化。在一名FUSP525L突变的ALS患者身上，研究人员提供了初步证据，反复鞘内注射ION363降低了中枢神经系统中野生型和突变型FUS的水平，导致作为疾病病理标志的FUS聚集物明显减少。在小鼠遗传学和人类临床研究中，研究人员提供的证据支持将FUS沉默作为FUS依赖性ALS和FTD的治疗策略。

据悉，FUS是一种RNA结合蛋白，在遗传和病理上与罕见的侵袭性ALS和FTD有关。

附：英文原文

Title: Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis

Author: Korobeynikov, Vladislav A., Lyashchenko, Alexander K., Blanco-Redondo, Beatriz, Jafar-Nejad, Paymaan, Shneider, Neil A.

Issue&Volume: 2022-01-24

Abstract: 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.

DOI: 10.1038/s41591-021-01615-z

Source: https://www.nature.com/articles/s41591-021-01615-z

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex