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

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, C Frank Bennett
{"title":"Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series","authors":"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, C Frank Bennett","doi":"10.1016/s0140-6736(25)00513-6","DOIUrl":null,"url":null,"abstract":"<h3>Background</h3>Pathogenic variants of fused in sarcoma (<em>FUS</em>) cause amyotrophic lateral sclerosis (<em>FUS</em>-ALS), with evidence of gain of function. Jacifusen is an antisense oligonucleotide targeting <em>FUS</em> 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 <em>FUS</em>-ALS.<h3>Methods</h3>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 <em>FUS</em> 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.<h3>Findings</h3>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.<h3>Interpretation</h3>The findings suggest the safety and possible efficacy of jacifusen for treating <em>FUS</em>-ALS. The efficacy of jacifusen is being further evaluated in an ongoing clinical trial.<h3>Funding</h3>ALS Association, Project ALS, Ionis Pharmaceuticals, Tow Foundation, Nancy D Perlman and Thomas D Klingenstein Innovation Fund for Neurodegenerative Disease, National Institutes of Health, Angel Fund for ALS Research, Cellucci Fund for ALS Research, Max Rosenfeld ALS Fund, University of Minnesota, and the Muscular Dystrophy Association.","PeriodicalId":22898,"journal":{"name":"The Lancet","volume":"33 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Lancet","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/s0140-6736(25)00513-6","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

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.

Funding

ALS Association, Project ALS, Ionis Pharmaceuticals, Tow Foundation, Nancy D Perlman and Thomas D Klingenstein Innovation Fund for Neurodegenerative Disease, National Institutes of Health, Angel Fund for ALS Research, Cellucci Fund for ALS Research, Max Rosenfeld ALS Fund, University of Minnesota, and the Muscular Dystrophy Association.
反义寡核苷酸jacifusen治疗FUS-ALS:一个研究者发起的、多中心的、开放标签的病例系列
融合肉瘤(FUS)的致病性变异导致肌萎缩侧索硬化症(FUS- als),并有证据表明其功能获得。Jacifusen是一种靶向FUS前mrna的反义寡核苷酸,先前在小鼠模型中显示可以延缓神经退行性变,并在首次人体研究中显示可能减缓功能衰退。在这里,我们寻求进一步评估使用jacifusen作为治疗FUS-ALS。方法: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,开展了扩大可及性项目。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,我们招募了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。研究结果提示jacifusen治疗FUS-ALS的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。资助:渐冻人协会、渐冻人项目、Ionis制药公司、Tow基金会、Nancy D Perlman和Thomas D Klingenstein神经退行性疾病创新基金、美国国立卫生研究院、渐冻人研究天使基金、Cellucci渐冻人研究基金、Max Rosenfeld渐冻人基金、明尼苏达大学和肌肉萎缩症协会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信