美国哥伦比亚大学欧文医学中心Neil A Shneider团队研究了反义寡核苷酸治疗肌萎缩侧索硬化症的疗效与安全性。相关论文于2025年5月22日发表在《柳叶刀》杂志上。

融合肉瘤（FUS）的致病性变体可导致肌萎缩侧索硬化症（FUS-ALS），并有功能获得的证据。Jacifusen是一种靶向FUS前mRNA的反义寡核苷酸，之前在小鼠模型中显示出延缓神经退行性变的作用，并在首次人体研究中可能减缓功能衰退。研究组试图进一步评估使用jacifusen作为FUS-ALS的治疗方法。

这一扩大获取方案是通过在5个地点（美国4家医院和瑞士1家医院）进行的一系列单患者研究性新药申请进行的。参与者携带FUS变异，如果没有ALS诊断，则有运动神经元疾病发病或电生理异常的临床证据。如果受试者长期通气并气管切开术，则不符合条件。受试者按顺序入组，在2.8 - 33.9个月内连续接受鞘内注射jacifusen。根据多次递增剂量的jacifusen（从20 mg到120 mg），随着安全性和其他数据的获得，对后续方案进行了修改，最后入选的参与者从治疗开始每月接受120 mg剂量。使用不良事件通用术语标准4.0版和标准脑脊液（CSF）指标评估安全性。脑脊液中神经丝轻链（NfL）的浓度被用作轴突损伤和神经退行性变的生物标志物，ALS功能评定量表-修订版（ALSFRS-R）评分被用作运动功能的整体测量。对死后CNS组织进行生化分析和免疫组织化学染色，定量FUS蛋白表达，评估FUS病理负担。

在2019年6月11日至2023年6月2日期间，该团队招募了12名参与者(中位年龄26岁[范围16-45岁]；其中7名（58%）为女性，5名（42%）为男性。脑脊液中细胞计数或总蛋白浓度的短暂升高（6名[50%]参与者）与治疗时间无关。最常见的不良事件是背部疼痛（6例[50%]）、头痛（4例[33%]）、恶心（3例[25%]）和腰椎穿刺后头痛（3例[25%]）。研究期间记录了两名参与者的死亡，均被认为与研究药物无关。治疗6个月后，脑脊液中NfL浓度降低82.8%。虽然大多数参与者在开始使用jacifusen治疗后功能持续下降（根据ALSFRS-R测量），但有一人在10个月后表现出前所未有的客观功能恢复，另一人则无症状，记录显示肌电异常有所改善。四名参与者的中枢神经系统组织样本的生化和免疫组织化学分析显示，FUS蛋白水平降低，FUS病理负担明显减轻。

研究结果表明，jacifusen治疗FUS-ALS具有安全性和可能的有效性。一项正在进行的临床试验正在进一步评估jacifusen的疗效。

附：英文原文

Title: Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series

Author: Neil A Shneider, Matthew B Harms, Vlad A Korobeynikov, Olivia M Rifai, Benjamin N Hoover, Elizabeth A Harrington, Sonya Aziz-Zaman, Jessica Singleton, Arish Jamil, Vikram R Madan, Ikjae Lee, Jinsy A Andrews, Richard M Smiley, Mahabub M Alam, Lauren E Black, Minwook Shin, Jonathan K Watts, David Walk, Daniel Newman, Robert M Pascuzzi, Markus Weber, Christoph Neuwirth, Sandrine Da Cruz, Armand Soriano, Roger Lane, Scott Henry, Joel Mathews, Paymaan Jafar-Nejad, Dan Norris, Frank Rigo, Robert H Brown, Stephan Miller, Rebecca Crean, C Frank Bennett

Issue&Volume: 2025-05-22

Abstract:

Background

Pathogenic variants of fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (FUS-ALS), with evidence of gain of function. Jacifusen is an antisense oligonucleotide targeting FUS pre-mRNA, previously shown to delay neurodegeneration in a mouse model and potentially slow functional decline in a first-in-human study. Here, we sought to further evaluate use of jacifusen as a treatment for FUS-ALS.

Methods

This expanded access programme was conducted through a series of single-patient investigational new drug applications at five sites (four hospitals in the USA and one in Switzerland). Participants carried a FUS variant and had clinical evidence of motor neuron disease onset or electrophysiological abnormalities, if not a diagnosis of ALS. Participants were ineligible if chronically ventilated with tracheostomy. Enrolled sequentially, participants received serial intrathecal injections of jacifusen over 2·8–33·9 months. Based on multiple ascending doses of jacifusen (from 20 mg to 120 mg), successive protocols were modified as safety and other data were acquired, with the last participants enrolled receiving 120 mg doses monthly from the start of their treatment. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and standard cerebrospinal fluid (CSF) metrics. Concentration of neurofilament light chain (NfL) in CSF was used as a biomarker of axonal injury and neurodegeneration, and the ALS Functional Rating Scale-Revised (ALSFRS-R) score was used as an overall measure of motor function. Biochemical analysis and immunohistochemical staining were done on post-mortem CNS tissues to quantify FUS protein expression and assess the burden of FUS pathology.

Findings

Between June 11, 2019, and June 2, 2023, we recruited 12 participants (median age 26 years [range 16–45]; seven [58%] were female and five [42%] were male) into the expanded access programme. Transient elevations in cell counts or total protein concentration in CSF (six [50%] participants) were unrelated to treatment duration. The most common adverse events were back pain (six [50%]), headache (four [33%]), nausea (three [25%]), and post-lumbar puncture headache (three [25%]). Two participant deaths were recorded during the programme, both thought to be unrelated to the investigational drug. The concentration of NfL in CSF was reduced by up to 82·8% after 6 months of treatment. Although most participants had continued functional decline (as measured by ALSFRS-R) after starting treatment with jacifusen, one showed unprecedented, objective functional recovery after 10 months, and another remained asymptomatic, with documented improvement in electromyographic abnormalities. Biochemical and immunohistochemical analysis of CNS tissue samples from four participants showed reduced FUS protein levels and an apparent decrease in the burden of FUS pathology.

Interpretation

The findings suggest the safety and possible efficacy of jacifusen for treating FUS-ALS. The efficacy of jacifusen is being further evaluated in an ongoing clinical trial.

DOI: 10.1016/S0140-6736(25)00513-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00513-6/abstract