Summary: An experimental antisense therapy targeting FUS gene mutations has produced unexpectedly strong clinical improvements in some patients with a rare, aggressive form of amyotrophic lateral sclerosis (ALS). The treatment reduces production of toxic FUS proteins in motor neurons, lowering biomarkers of neurodegeneration and, in a few cases, restoring lost function and extending survival.
In a case series of patients treated under expanded access, two individuals experienced striking benefits—one regained independent walking and breathing, and another has remained symptom-free for three years. Across treated participants, levels of neurofilament light, a marker of nerve injury, fell dramatically after treatment.
Key Facts:
- Targeted approach: The therapy uses antisense oligonucleotides to silence the FUS gene, reducing production of toxic FUS protein in motor neurons.
- Clinical improvement: Some patients experienced functional recovery—an uncommon outcome in ALS studies.
- Biomarker response: Cerebrospinal fluid neurofilament light fell by as much as 83% after six months, suggesting reduced neuronal injury.
Source: Columbia University
Columbia neurologist and researcher Neil Shneider is careful and direct when discussing experimental options with his ALS patients.
“Patients always ask, ‘What can I hope to get out of this?’” Shneider says. “For most clinical trials, our realistic expectation is slowing or halting disease progression, not recovery.”
That is why the improvements observed in some patients treated with a drug developed from Shneider’s work were so surprising and encouraging.
“In ALS drug development, we rarely expect measurable improvements in function,” Shneider explains. “Yet one patient in this series showed an unprecedented functional recovery. That outcome is both surprising and deeply motivating for researchers and families affected by ALS.”
Notable individual outcomes
The report describes 12 patients treated with ulefnersen (initially known as jacifusen), an antisense therapy designed to reduce FUS protein production. Mutations in the FUS gene account for roughly 1–2% of ALS cases but often produce aggressive disease that begins in adolescence or young adulthood. In these patients, mutant FUS proteins accumulate in motor neurons and eventually cause neuronal death.
Two patients in the case series stood out. A young woman treated since late 2020 regained the ability to walk without assistance and to breathe without a ventilator—abilities lost to her ALS—and now has survived longer with juvenile-onset FUS-ALS than any previously documented patient. A man in his mid-30s began treatment before symptoms appeared; over three years of continuous therapy he has not developed clinical ALS, and abnormal muscle electrical activity has improved.
Overall, participants showed reductions in cerebrospinal fluid neurofilament light of up to 82.8% after six months, consistent with lower rates of axonal injury. While most symptomatic patients continued to decline, several experienced slower progression and extended survival compared with expected trajectories for this aggressive form of ALS.
“These responses demonstrate that timely intervention against a clearly defined genetic target can not only slow disease but, in some cases, reverse functional loss,” Shneider says. “This is a clear example of precision medicine guided by biology.”
The series also reported that the drug was generally well tolerated: no serious adverse events were attributed to the therapy. Common side effects included back pain, headache, nausea, and post-lumbar puncture headache; transient cerebrospinal fluid changes were observed in some participants.
Following encouraging early outcomes, Ionis Pharmaceuticals agreed to sponsor a global, investigator-led clinical trial of ulefnersen that is now underway, with investigators awaiting broader trial results and potential regulatory approval.
Development and rationale for ulefnersen
Ulefnersen began as a targeted effort to help an individual patient and evolved into a treatment now delivered to dozens of people under expanded access. Shneider first administered the therapy to Jaci Hermstad after collaborating with Ionis to develop an antisense oligonucleotide (ASO) aimed at lowering FUS expression. Preclinical studies in mice showed that reducing FUS levels delayed neurodegeneration, and laboratory evidence suggested that mature neurons tolerate partial reduction of normal FUS protein—supporting the strategy of gene silencing for FUS-ALS.
In 2019, Shneider obtained FDA permission to provide ulefnersen through expanded access. Since that time, at least 25 patients worldwide have received the therapy under compassionate-use programs, including the 12 reported in the Lancet case series.
Additional information
The study, titled “Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series,” was published online in the Lancet on May 22, 2025.
Authors (Columbia University unless noted): Neil A Shneider, Matthew B Harms, Vlad A Korobeynikov, Olivia M Rifai, Benjamin N Hoover, Elizabeth A Harrington, Sonia Aziz-Zaman, Jessica Singleton, Arish Jamil, Vikram R Madan, Ikjae Lee, Jinsy A Andrews, Richard M Smiley, Mahabub M Alam, Lauren E Black (Charles River Laboratories), Minwook Shin (Sookmyung Women’s University, Korea), Jonathan K Watts (University of Massachusetts Chan Medical School), David Walk (University of Minnesota Medical School), Daniel Newman (Henry Ford Hospital), Robert M Pascuzzi (Indiana University School of Medicine), Markus Weber (Kantonsspital St. Gallen, Switzerland), Christopher Neuwirth (Kantonsspital), Sandrine Da Cruz (Leuven Brain Institute, Belgium), Armand Soriano (Ionis Pharmaceuticals), Roger Lane (Ionis), Scott Henry (Ionis), Joel Matthews (Ionis), Paymaan Jafar-Nejad (Ionis), Dan Norris (Ionis), Frank Rigo (Ionis), Robert H Brown (Ionis), Stephan Miller (Ionis), Rebecca Crean (Ionis), and C Frank Bennett (Ionis).
Funding: This research received support from the ALS Association (ALSA CU20-1073), Project ALS, Ionis Pharmaceuticals, the Tow Foundation, the Nancy D. Perlman and Thomas D. Klingenstein Innovation Fund for Neurodegenerative Disease, the National Institutes of Health (R01NS106236, TL1TR001875, R01NS111990, UL1TR001873), the American Academy of Neurology, the American Brain Foundation, the CReATe Consortium, the Angel Fund for ALS Research, the Cellucci Fund, the Max Rosenfeld ALS Fund, the University of Minnesota, and the Muscular Dystrophy Association. Neil Shneider received research funding from Ionis Pharmaceuticals for this investigator-initiated study; additional disclosures are available in the published paper.
About this ALS and neuropharmacology research news
Author: Helen Garey
Source: Columbia University
Contact: Helen Garey – Columbia University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series” by Neil Shneider et al., Lancet.
Abstract
Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series
Background
Pathogenic variants in fused in sarcoma (FUS) cause a form of ALS (FUS-ALS) through apparent gain-of-function mechanisms. Jacifusen (ulefnersen) is an antisense oligonucleotide targeting FUS pre-mRNA. Preclinical mouse studies showed delayed neurodegeneration, and early human use suggested potential to slow functional decline. This series further evaluates jacifusen in people with FUS-ALS.
Methods
This expanded access program used single-patient investigational new drug applications at five sites (four U.S. hospitals and one in Switzerland). Enrolled participants carried FUS variants and had clinical or electrophysiological evidence of motor neuron disease. Those chronically ventilated with a tracheostomy were excluded. Participants received repeated intrathecal injections over 2.8–33.9 months with dose escalation from 20 mg to 120 mg; later participants received monthly 120 mg dosing. Safety was monitored by standard criteria and CSF measures. Neurofilament light (NfL) in CSF served as a biomarker of axonal injury, and the ALS Functional Rating Scale–Revised (ALSFRS-R) was used to track motor function. Post-mortem CNS tissue analysis quantified FUS protein and pathology burden.
Findings
From June 11, 2019, to June 2, 2023, 12 participants were enrolled (median age 26 years, range 16–45; seven female, five male). Some participants showed transient CSF changes unrelated to treatment duration. The most common adverse events were back pain, headache, nausea, and post-lumbar puncture headache. Two deaths occurred and were considered unrelated to the drug. CSF NfL concentrations fell by up to 82.8% after six months. While most participants continued to experience functional decline, one showed objective functional recovery after 10 months and another remained asymptomatic with improved electromyographic findings during three years of treatment. Post-mortem analyses from four participants showed reduced FUS protein levels and diminished FUS pathology.
Interpretation
These results support the safety and potential efficacy of jacifusen (ulefnersen) for treating FUS-ALS. Ongoing randomized trials will further evaluate clinical benefit.
Funding
Funding sources include the ALS Association, Project ALS, Ionis Pharmaceuticals, the Tow Foundation, the Nancy D. Perlman and Thomas D. Klingenstein Innovation Fund for Neurodegenerative Disease, the National Institutes of Health, the Angel Fund for ALS Research, the Cellucci Fund for ALS Research, the Max Rosenfeld ALS Fund, the University of Minnesota, and the Muscular Dystrophy Association.