Summary

A new experimental therapy targeting a rare and aggressive form of ALS linked to FUS gene mutations has unexpectedly resulted in some patients showing clinical improvements, such as regained mobility and extended life expectancy. This treatment employs antisense technology to suppress the FUS gene, which leads to a decrease in harmful protein buildup within motor neurons.

In a recent case series, two patients demonstrated astonishing results—one regained both walking and breathing without assistance, while another has remained symptom-free for three years. Additionally, the therapy led to a significant decrease in neurofilament light levels, a marker indicating nerve damage.

Key Facts

• Targeted Therapy: This treatment utilizes antisense oligonucleotides to silence the FUS gene and diminish toxic proteins.
• Unexpected Recovery: Certain patients exhibited functional enhancements, which is quite rare in ALS research.
• Biomarker Drop: Patients undergoing treatment showed a reduction of up to 83% in neurofilament light, signifying lowered nerve damage.

When talking to ALS patients who are part of experimental therapies, neurologist Neil Shneider is fully candid.

“Patients often ask me, ‘What can I expect from this?’” Shneider notes. “I reply that our aim is typically to slow the disease or maybe even stop its progression.”

Thus, it was unexpected when some patients receiving a novel drug—a result of Shneider’s research—exhibited improvements.

“When we test new drugs for ALS, clinical improvement isn’t something we anticipate,” Shneider explains.

Detailed reports from 12 patients treated with this new therapy, aimed at a rare ALS variant driven by a mutation in the FUS gene, were published by Shneider in a recent issue of The Lancet.

While FUS mutations account for around 1% to 2% of ALS instances, they tend to lead to some of the most aggressive forms, often appearing in adolescents and young adults. In affected individuals, toxic FUS proteins build up in motor neurons, leading to their eventual death.

In the published reports, two patients had remarkable responses to the treatment called ulefnersen (formerly known as jacifusen), developed in collaboration with Ionis Pharmaceuticals.

One young woman, who began treatment in late 2020, regained the ability to walk without help and breathe without a ventilator, both capabilities lost due to ALS. She has outlived any previous known patients suffering from this severe juvenile-onset version of FUS ALS.

The second patient, a man in his mid-30s, was free of symptoms at the start of treatment, despite tests suggesting that symptoms were likely to develop soon.

After three years on the experimental drug, he remains asymptomatic, with marked improvement in the abnormal electrical activity in his muscles.

Overall, patients from the series experienced up to an 83% decrease in the neurofilament light protein after just six months of treatment.

“These results imply that if we act early and target the right issue timely within the disease timeline, we might not only slow disease progression but potentially reverse some functional declines,” Shneider remarks.

“This exemplifies precision medicine and therapeutic advances grounded in scientific understanding of disease biology.”

Although most symptomatic patients in the series faced severe declines from their aggressive illness, Shneider believes several benefited from the treatment. Their disease progression slowed, allowing them to live longer.

The case series also indicated the drug’s safety, showing no significant negative effects linked to the treatment.

Based on initial findings, Ionis Pharmaceuticals has pledged support for a global clinical trial of ulefnersen, which is currently underway.

“We are looking forward to those results, which we hope will lead to ulefnersen being approved,” Shneider said.

The Story Behind Ulefnersen

The journey to develop ulefnersen began with the aim of assisting a specific patient and has evolved into a large-scale clinical trial that may benefit numerous patients facing this aggressive form of ALS.

Shneider first tested this therapy six years ago on a patient named Jaci Hermstad from Iowa, whose identical twin had succumbed to the disease years before. Collaborating with Ionis Pharmaceuticals, Shneider attempted to formulate a drug that could potentially delay Jaci’s symptoms.

He had substantial reasons to be optimistic. His preliminary research on mice had established that FUS mutations lead to the generation of proteins harmful to motor neurons. The findings hinted that lowering toxic FUS protein levels could impede or defer the onset and progression of ALS.

Shneider speculated that the drug could effectively reduce FUS proteins. It belongs to an emerging class of medications that employ short strands of DNA, termed antisense oligonucleotides (ASOs), to silence particular genes and stop the synthesis of the proteins they produce.

Designed to silence the FUS gene, ulefnersen aims to decrease both toxic and normal FUS protein production.

“Our research also indicated that mature neurons can endure a decrease in normal FUS protein, which justified our treatment approach for patients with FUS-ALS,” Shneider adds.

In 2019, Shneider sought FDA permission to give ulefnersen to Jaci through an expanded access program, sometimes referred to as “compassionate use.”

Since that time, around 25 patients across the globe have been treated with ulefnersen (initially named jacifusen after Jaci Hermstad) in expanded access programs, including the dozen patients documented in The Lancet article.

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.

Funding for the study was provided by the ALS Association, Project ALS, Ionis Pharmaceuticals, and various other foundations and organizations.