小柯机器人

美国麻省大学医学院Robert H. Brown Jr、Jonathan K. Watts等研究人员合作发现，强效混合骨架的反义寡核苷酸可抑制突变体C9orf72的表达。相关论文于2021年12月23日在线发表于国际学术期刊《自然—医学》。

据研究人员介绍，C9ORF72基因的G₄C₂重复扩增是肌萎缩性脊髓侧索硬化症（ALS）和额颞叶痴呆症（FTD）的最常见遗传原因，这是两种毁灭性的成年发病型神经退行性疾病。

研究人员利用C9-ALS/FTD患者衍生的细胞和C9ORF72 BAC转基因小鼠，产生并优化了反义寡核苷酸（ASO），它能选择性地阻断含G₄C₂重复的转录本表达，并有效抑制聚(GP)二肽的组织水平。减少硫代磷酸酯含量的ASO显示出更好的耐受性而不影响疗效。在一名携带有G₄C₂重复扩增的突变体C9ORF72患者中，通过鞘内给药的方式重复给药的最佳ASO具有良好的耐受性，导致脑脊液中的聚(GP)水平显著降低。该研究提供了关于核酸化学对毒性影响的见解，并首次证明了临床抑制C9ORF72基因的可行性。目前需要进行更多的临床试验来证明这种疗法对C9ORF72基因突变患者的安全性和有效性。

附：英文原文

Title: Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide

Author: Tran, Hlne, Moazami, Michael P., Yang, Huiya, McKenna-Yasek, Diane, Douthwright, Catherine L., Pinto, Courtney, Metterville, Jake, Shin, Minwook, Sanil, Nitasha, Dooley, Craig, Puri, Ajit, Weiss, Alexandra, Wightman, Nicholas, Gray-Edwards, Heather, Marosfoi, Miklos, King, Robert M., Kenderdine, Thomas, Fabris, Daniele, Bowser, Robert, Watts, Jonathan K., Brown, Robert H.

Issue&Volume: 2021-12-23

Abstract: Expansions of a G4C2 repeat in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset neurodegenerative disorders. Using C9-ALS/FTD patient-derived cells and C9ORF72 BAC transgenic mice, we generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G4C2 repeat-containing transcripts and effectively suppress tissue levels of poly(GP) dipeptides. ASOs with reduced phosphorothioate content showed improved tolerability without sacrificing efficacy. In a single patient harboring mutant C9ORF72 with the G4C2 repeat expansion, repeated dosing by intrathecal delivery of the optimal ASO was well tolerated, leading to significant reductions in levels of cerebrospinal fluid poly(GP). This report provides insight into the effect of nucleic acid chemistry on toxicity and, to our knowledge, for the first time demonstrates the feasibility of clinical suppression of the C9ORF72 gene. Additional clinical trials will be required to demonstrate safety and efficacy of this therapy in patients with C9ORF72 gene mutations. An antisense oligonucleotide targets mutant transcripts of the ALS gene C9orf72, suppressing the poly(GP) dipeptide in tissues in mice and in the spinal fluid of a single patient harboring the C9orf72 gene mutation

DOI: 10.1038/s41591-021-01557-6

Source: https://www.nature.com/articles/s41591-021-01557-6

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