FUS-Mutated Amyotrophic Lateral Sclerosis · FUS-ALS

What this is

FUS-mutated amyotrophic lateral sclerosis is a familial subtype of ALS caused by mutations in the FUS gene, which encodes an RNA-binding protein involved in transcription, RNA splicing, and DNA repair. The protein is normally located in the cell nucleus. Disease-causing FUS variants disrupt a nuclear localization signal at the protein's C-terminus, causing the mutant protein to mislocalize to the cytoplasm, where it forms toxic aggregates that progressively damage motor neurons.

FUS-ALS accounts for approximately 1 to 2 percent of all ALS cases and approximately 4 to 5 percent of familial ALS cases. The clinical course is typically more aggressive than non-genetic ALS, with earlier onset and faster progression. Some FUS variants, including the P525L variant, produce a juvenile or young-adult-onset form with onset in the teens or twenties and a course measured in months rather than years. The disease is uniformly fatal in the absence of effective therapy, with most affected individuals dying from respiratory failure within one to three years of symptom onset for the aggressive variants.

Diagnosis is by clinical examination consistent with ALS combined with FUS sequencing on a familial-ALS gene panel. The disease was first molecularly characterized in 2009. There is no approved disease-modifying therapy as of mid-2025; tofersen, the first ASO approved for a familial ALS subtype (SOD1-mutant), was approved in 2023 for a different genetic form of the disease.

The case

Jaci and Alex Hermstad were identical twins born in Iowa in approximately 1993. Both carried the heterozygous FUS P525L variant, the same aggressive juvenile-onset FUS mutation that produces ALS in childhood or early adulthood. Alex Hermstad developed symptoms in adolescence and died of FUS-ALS in 2011 at age 17. Jaci, who shared the same variant and the same identical-twin genetics, lived without symptoms for most of her twenties.

In February 2019, at age 26, Jaci was diagnosed with FUS-ALS. She had begun to develop the same neuromuscular weakness that had killed her sister eight years earlier. The Hermstad family connected with Neil Shneider, a neurologist and neuroscientist at Columbia University Medical Center who had been studying FUS-ALS in collaboration with Ionis Pharmaceuticals. Shneider's group at Columbia had been working with Ionis on an ASO designed to knock down expression of mutant FUS messenger RNA, a strategy intended to reduce the toxic aggregate burden on motor neurons.

The drug, ION363, had not yet entered formal clinical trials. The combination of Jaci's rapid progression, her family's prior loss of an identical twin to the same disease, and ION363 being the only therapeutic option in active development for FUS-ALS made the case for compassionate-use access. Shneider requested permission from the FDA to administer ION363 to Jaci through the agency's expanded-access pathway. The drug was renamed jacifusen in her honor.

Jaci received her first intrathecal dose of jacifusen in June 2019, four months after her diagnosis. The team continued dosing through the rest of 2019 and into early 2020. The drug appeared to slow but did not halt her disease progression. Jaci died on May 1, 2020, approximately ten months after her first dose, at age 27.

The case did not end with Jaci's death. Shneider and the FUS-ALS clinical community had begun receiving requests from other families with the same genetic disease. Beginning in 2019 and continuing through 2023, twelve participants with FUS-ALS received jacifusen through a series of investigator-initiated, multi-center, open-label expanded-access INDs. Some, like Jaci, were dosed after substantial disease progression and showed slowing but not reversal. At least one participant who began treatment earlier in her disease course showed a remarkable response: she recovered the ability to walk unaided and the ability to breathe without ventilator support, both of which she had previously lost.

The twelve-patient case series was published as a peer-reviewed paper in The Lancet on May 22, 2025, by Shneider, Harms, Korobeynikov, and colleagues. The headline finding was that intrathecal jacifusen produced reductions of up to 82.8 percent in cerebrospinal fluid neurofilament light chain, a biomarker of neuronal damage, by six months of treatment. Some participants showed slowing or apparent reversal of clinical decline; others, particularly those treated late in disease, did not.

The research

Jacifusen, also known as ION363 and ulefnersen, is a 2'-O-methoxyethyl phosphorothioate gapmer antisense oligonucleotide developed by Ionis Pharmaceuticals in collaboration with Neil Shneider's lab at Columbia. The mechanism of action is RNase H-mediated cleavage of FUS messenger RNA. Reducing total FUS protein in motor neurons is intended to reduce both the wild-type pool and the mutant pool, with the therapeutic effect coming from the reduction in toxic mutant aggregates. The chemistry class is the same chemistry that produced nusinersen for spinal muscular atrophy and the broader Ionis ASO catalog.

The preclinical proof of concept was published by Korobeynikov, Lyashchenko, Hammer, and others, with Shneider as senior author, in Nature Medicine on January 24, 2022. The paper described the development of FUS-ALS mouse models carrying the P525L and other pathogenic FUS variants and demonstrated that ASO-mediated knockdown of FUS in those models reduced the toxic protein aggregates and slowed motor neuron degeneration.

Funding for the early Columbia work came partly from the ALS Association and Project ALS, both of which contributed to the case series and to the broader Columbia FUS-ALS research program. The Hermstad family's advocacy, both before and after Jaci's death, has continued to shape the program; Jaci's name on the drug is the most public version of that influence.

Following the publication of the Lancet case series in 2025, Ionis announced plans to advance ION363 into a formal phase 3 randomized clinical trial. The phase 3 trial is intended to provide the controlled-arm data the case series did not, and to support a regulatory submission for FDA approval of jacifusen for FUS-ALS. The patient population is small enough that the phase 3 design will need to use historical-control comparators or other adaptive features, and the case series itself will likely contribute to the regulatory package.

What is blocking the next case

The FUS-ALS field has shifted between 2019 and 2025 from compassionate-use single-patient programs to a formal industry-led phase 3 trial. The blockers for the next FUS-ALS case are correspondingly different from the blockers for, say, the next single-patient KAND program.

The first blocker is patient identification and timing. The case series and other published data suggest that earlier intervention produces better outcomes, including the participant who recovered walking and breathing capacity she had previously lost. Identifying FUS carriers before symptom onset, particularly among siblings of affected individuals or in families with known FUS variants, would allow pre-symptomatic dosing. The infrastructure for genetic counseling, predictive testing, and pre-symptomatic intervention in familial ALS exists in only a handful of academic centers.

The second blocker is the phase 3 trial itself. ALS trials in general are difficult to power; the disease progresses too fast to use long enrollment windows, the patient population is heterogeneous, and the rate of symptomatic progression varies. A FUS-ALS-specific trial has the advantage of a more uniform genetic cohort but the disadvantage of a smaller absolute population. The trial design Ionis is now developing has to thread these constraints.

The third blocker is access for affected individuals not enrolled in the trial. The Lancet case series and the expanded-access INDs that produced it set a precedent for compassionate use, but the formal phase 3 program will likely restrict additional expanded-access dosing to particular criteria. Families whose affected members do not qualify for the trial face the same difficult access questions that all rare-disease families face once a drug is in late development but not yet approved.

Where this connects

The chemistry that made jacifusen possible is the chemistry described in How splice-switching ASOs work, although jacifusen uses gapmer chemistry and the RNase H mechanism rather than splice modulation. The institutional precedent that made splice-switching ASOs into a mature drug class, and made the Ionis chemistry platform deployable for n-of-1 and n-of-few cases like FUS-ALS, is described in Adrian Krainer and the splicing mechanism that became Spinraza. The broader regulatory framework the FUS-ALS program now operates within is described in What an n-of-1 trial actually is.

Sources

• Shneider NA, Harms MB, Korobeynikov VA, et al. Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series. Lancet. 2025;405(10495):2075-2086. PMID: 40414239.
• Korobeynikov VA, Lyashchenko AK, Blanco-Redondo B, et al; Shneider NA, senior author. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med. 2022;28(1):104-116.
• Columbia University Irving Medical Center. Promising ALS therapy moves closer to clinic. 2025.
• The ALS Association and Project ALS. Press materials on funding for the Columbia FUS-ALS program. 2019-2025.
• ALS News Today. Ionis opening phase 3 trial of ION363, antisense therapy for FUS-ALS. 2025.
• Vagelos College of Physicians and Surgeons. ALS: treatment for one opens door for others. Columbia Medicine, Fall/Winter 2020. (Profile of Shneider's program and Jaci Hermstad's case.)
• Project ALS. New model and gene targeting approach show promise for ALS therapies. Article on the jacifusen program.
• Charles River Laboratories Eureka blog. One Cowgirl's Fight Against ALS Rages On. (Profile of Jaci and the Hermstad family's advocacy.)