Summary: A groundbreaking experimental therapy for a rare, aggressive form of ALS caused by FUS gene mutations has produced surprising clinical improvements in some patients, including restored mobility and extended survival. The treatment uses antisense technology to silence the FUS gene, reducing toxic protein buildup in motor neurons.
Two patients in a recent case series showed remarkable responses—one regained the ability to walk and breathe unassisted, while another has remained symptom-free for three years. The therapy also significantly reduced neurofilament light levels, a biomarker of nerve damage.
Key Facts:
- Targeted Therapy: The treatment uses antisense oligonucleotides to silence the FUS gene and reduce toxic proteins.
- Unexpected Recovery: Some patients showed functional improvement, a rare outcome in ALS research.
- Biomarker Drop: Treated patients had up to an 83% reduction in neurofilament light, indicating reduced nerve damage.
Source: Columbia University
When Columbia neurologist and scientist Neil Shneider speaks to his ALS patients who volunteer for experimental therapies, he’s unwaveringly honest.
“Patients always ask me, “What can I hope to get out of this?” Shneider says. “And I always say, in most clinical trials, our hope is that we can slow the disease or maybe even halt progression.”
So it was a big surprise when some of the patients treated with an experimental drug—a therapy that emerged from Shneider’s research efforts—showed improvements.
“When testing new drugs for ALS, we do not expect to see clinical improvement,” Shneider says.
“What we’ve seen in one patient is really unprecedented functional recovery. It’s surprising and deeply motivating for us, the ALS research community, but also the community of ALS patients.”
Remarkable success stories
Data from 12 patients—all treated with the novel therapy for a rare form of ALS caused by a genetic mutation in a gene called FUS—were presented in a case series published by Shneider online in the Lancet.
Though these gene mutations are responsible for only 1% to 2% of ALS cases, they cause some of the most aggressive forms of ALS that begin in adolescents and young adults. In patients with these mutations, toxic FUS proteins accumulate in the motor neurons that control the patient’s muscles, eventually killing the neurons.
Two of the patients in the published case series showed a remarkable response to the experimental therapy, ulefnersen (previously known as jacifusen), developed by Shneider in collaboration with Ionis Pharmaceuticals.
One young woman, who has received injections of the therapy since late 2020, recovered the ability to walk unaided and to breathe without the use of a ventilator, both previously lost to ALS. She has lived longer with this disease than any other known patient with this juvenile-onset form of FUS ALS.
The second patient, a man in his mid-30s, was asymptomatic when he began treatment, but tests of electrical activity in his muscles indicated that symptoms would likely emerge soon.
In three years of continuous treatment with the experimental drug, the man has yet to develop any symptoms of FUS-ALS and the abnormal electrical activity in his muscles has improved.
Overall, after six months of treatment, patients in the series experienced up to 83% decrease in a protein called neurofilament light, a biomarker of nerve damage.
“These responses show that if we intervene early enough and go after the right target at the right time in the course of disease, it’s possible to not only slow disease progression, but actually reverse some of the functional losses,” Shneider says.
“It’s also a wonderful example of precision medicine and therapeutic development based on science and an understanding of the biology of disease.”
Though most of the other symptomatic patients in the series did not survive their aggressive disease, Shneider says “several apparently benefited from the treatment. The progression of their disease slowed, and they lived a longer life as a consequence.”
The case series also showed that the drug is safe and well tolerated, with no serious adverse events related to the drug.
After seeing results from the first of these patients, Ionis Pharmaceuticals committed to sponsoring a global clinical trial of the drug, led by Shneider, which is now in progress.
“Now we are eagerly awaiting those results, which we hope will lead to the approval of ulefnersen,” Shneider said.
The story behind ulefnersen
The development of ulefnersen began as an effort to help a single patient and has grown into a full-scale clinical trial that could help many patients with this aggressive form of ALS.
Shneider first tested the therapy six years ago in a patient from Iowa, Jaci Hermstad, whose identical twin had died from the disease years earlier. Shneider worked with Ionis Pharmaceuticals to develop a drug, never tested in people, that might slow the progression of Jaci’s symptoms.
He had good reason to believe the drug might work. Just a few years earlier, his research in mice revealed that the FUS mutations cause cells to make proteins that are toxic to motor neurons. The results suggested that reducing levels of toxic FUS proteins could prevent or delay onset and progression of ALS.
Shneider believed the drug might be a powerful way to reduce FUS proteins. The drug belongs to an emerging and highly promising class that uses short pieces of DNA, called antisense oligonucleotides, or ASOs, to silence specific genes and halt the production of the proteins they encode.
Ulefnersen was designed to silence the FUS gene and reduce production of toxic and normal FUS proteins.
“Because we also found that mature neurons tolerate a reduction of normal FUS protein, our studies provided the rationale for treating FUS-ALS patients with this drug,” Shneider says.
In 2019, Shneider requested permission from the FDA to administer ulefnersen to Jaci through its expanded access program, sometimes called “compassionate use.”
Since then, at least 25 patients have been treated with ulefnersen (originally named jacifusen for Jaci Hermstad) around the world in expanded access programs, including the dozen patients described in the Lancet article.
Additional information
The study, ‘Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series,” was published online in the Lancet on May 22, 2025.
All authors (from Columbia University except where 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 InstituteBelgium), 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: The study was funded by grants from the ALS Association (ALSA CU20-1073), Project ALS, and Ionis Pharmaceuticals and with support from the Tow Foundation and the Nancy D Perlman and Thomas D Klingenstein Innovation Fund for Neurodegenerative Disease.
The study was also funded in part by grants from the National Institutes of Health (R01NS106236, TL1TR001875, R01NS111990, UL1TR001873), the American Academy of Neurology, the American Brain Foundation, and the CReATe Consortium, the Angel Fund for ALS Research, Cellucci Fund for ALS Research, Max Rosenfeld ALS Fund, the University of Minnesota, and the Muscular Dystrophy Association.
Neil Shneider has received research funding from Ionis Pharmaceuticals in support of this investigator-initiated study. Additional disclosures can be found in the 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 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.
