反义寡核苷酸治疗对C9orf72相关ALS的分子影响，这一成果由美国埃默里大学Jonathan D. Glass课题组经过不懈努力而取得。相关论文于2025年8月26日发表于国际顶尖学术期刊《细胞》杂志上。

研究小组确定靶点参与中枢神经系统（CNS）的程度，并阐明治疗后脑脊液（CSF）生物标志物的药效学。BIIB078治疗病例的脑脊液显示DPRs降低，炎症生物标志物持续增加，包括C-C基序趋化因子配体26（CCL26）。BIIB078广泛分布于死后中枢神经系统组织；然而，DPRs和磷酸化的TDP-43仍然丰富。治疗没有改变c9ALS脊髓的蛋白质组学特征，尽管观察到RNase T2丰度明显增加，与BIIB078浓度相关。尽管分布广泛，但BIIB078并未显著影响关键的中枢神经系统病理，这强调了鉴定反映ASO治疗后疾病相关神经病理变化的药理学生物标志物的必要性。

据了解，C9orf72相关肌萎缩性侧索硬化症（c9ALS）由内含子G4C2重复扩增引导，导致毒性RNA转录物和二肽重复蛋白（DPRs）。一项以反义寡核苷酸（ASO） BIIB078为靶点的临床试验因未能提供临床益处而中止。

附：英文原文

Title: Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS

Author: Zachary T. McEachin, Mingee Chung, Sabrina A. Stratton, Changhee Han, Woo Jae Kim, Udit Sheth, Eleanor V. Thomas, Ethan Issenberg, Tanvi Kamra, Paola Merino, Yona Levites, Nisha Raj, Eric B. Dammer, Duc M. Duong, Lingyan Ping, Anantharaman Shantaraman, Adam N. Trautwig, Joshna Gadhavi, Ezana Assefa, Marla Gearing, Kaylor M. Kelly, Shanu F. Roemer, Michael DeTure, Seneshaw Asress, Thomas Kukar, Christina Fournier, Dennis W. Dickson, Leonard Petrucelli, Todd E. Golde, Bjrn Oskarsson, Tania F. Gendron, Nicholas T. Seyfried, Jonathan D. Glass

Issue&Volume: 2025-08-26

Abstract: C9orf72-associated amyotrophic lateral sclerosis (c9ALS) is caused by an intronic G4C2 repeat expansion that leads to toxic RNA transcripts and dipeptide repeat proteins (DPRs). A clinical trial using the antisense oligonucleotide (ASO) BIIB078 to target these transcripts was discontinued after failing to provide clinical benefit. Here, we determine the extent of target engagement in the central nervous system (CNS) and elucidate pharmacodynamic cerebrospinal fluid (CSF) biomarkers following treatment. CSF from BIIB078-treated cases showed reduced DPRs and sustained increases in inflammatory biomarkers, including C-C motif chemokine ligand 26 (CCL26). BIIB078 was widely distributed in postmortem CNS tissue; however, DPRs and phosphorylated TDP-43 remained abundant. Proteomic signatures in c9ALS spinal cord were not altered with treatment, although a distinct increase in RNase T2 abundance that correlated with BIIB078 concentration was observed. Thus, despite widespread distribution, BIIB078 did not significantly impact key CNS pathologies, emphasizing the need to identify pharmacodynamic biomarkers that reflect disease-relevant neuropathological changes in response to ASO therapies.

DOI: 10.1016/j.cell.2025.07.045

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00908-0