THE INVESTIGATIONAL antisense oligonucleotide jacifusen has shown promising safety and early signs of efficacy in patients with FUS-ALS, including unprecedented functional recovery in some cases, according to a multicentre open-label case series.
FUS-associated amyotrophic lateral sclerosis (FUS-ALS) is a rare, aggressive form of motor neurone disease caused by mutations in the FUS gene, leading to toxic protein accumulation and rapid neurodegeneration, often affecting adolescents and young adults. Standard treatments offer limited benefit, and there is urgent need for targeted therapies. Jacifusen, an antisense oligonucleotide, is designed to silence the FUS gene and reduce harmful protein production. Previous studies in animal models and a first-in-human trial suggested that jacifusen could delay neurodegeneration and slow functional decline, prompting further evaluation in this expanded access programme.
Between June 2019 and June 2023, twelve participants (median age 26 years, range 16–45; 58% female) with confirmed FUS mutations and clinical or electrophysiological evidence of motor neurone disease received serial intrathecal injections of jacifusen at five sites in the USA and Switzerland. Dosing protocols were adapted over time, with later participants receiving 120 mg monthly. The most common adverse events were back pain (50%), headache (33%), nausea (25%), and post-lumbar puncture headache (25%); no serious adverse events were attributed to the drug. Two deaths occurred, both unrelated to treatment. Importantly, neurofilament light chain (NfL) concentrations in cerebrospinal fluid—a biomarker of nerve injury—were reduced by up to 83% after six months of treatment. While most participants experienced continued functional decline, one patient achieved remarkable recovery, regaining mobility and respiratory independence after ten months, and another remained asymptomatic with improved electromyographic findings. Post-mortem analysis of central nervous system tissue from four participants revealed reduced FUS protein levels and decreased pathological burden.
These findings provide early evidence that jacifusen is safe and may offer clinical benefits for patients with FUS-ALS, a population with limited treatment options and poor prognosis. For clinical practice, this case series highlights the potential of precision genetic therapies to alter the course of aggressive neurodegenerative diseases. Larger, controlled trials are now underway to confirm efficacy and inform future use. Clinicians should remain alert to advances in antisense oligonucleotide therapies, as they may soon offer new hope for patients with rare genetic forms of ALS.
Reference
Shneider NA et al. Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series. The Lancet. 2025;DOI:10.1016/S0140-6736(25)00513-6.
