In a remarkable departure from the typical expectations of neurodegenerative disease trials, an experimental therapy targeting a rare genetic form of amyotrophic lateral sclerosis (ALS) has yielded unprecedented functional recoveries in some patients. The therapeutic agent, ulefnersen—formerly known as jacifusen—was developed by Columbia University neurologist Dr. Neil Shneider in collaboration with Ionis Pharmaceuticals. Data published online in The Lancet reveal that two of the 12 patients treated for juvenile-onset FUS-mutant ALS experienced dramatic improvements, including the restoration of walking ability and respiratory independence, while another asymptomatic carrier has yet to develop disease signs after three years of continuous treatment.
Background: FUS-Mutant ALS and the Urgent Need for New Therapies
A Rare but Devastating Subtype of ALS
Amyotrophic lateral sclerosis is a progressive neurological disease characterized by the degeneration of motor neurons, leading to muscle weakness, paralysis, and eventually death, typically within three to five years of symptom onset. While the majority of ALS cases are sporadic, 5–10% arise from inherited genetic mutations. Among these, mutations in the FUS (FUsed in Sarcoma) gene account for approximately 1–2% of all cases but often present an especially aggressive clinical course when they occur in adolescents or young adults.
Mechanism of FUS Toxicity
FUS mutations lead to the production of aberrant proteins that accumulate in the cell nucleus and cytoplasm of motor neurons, triggering a cascade of cellular stress, impaired RNA processing, and ultimately cell death. Prior animal studies by Shneider and colleagues demonstrated that reducing overall FUS protein levels could mitigate neurotoxicity and improve motor function in mouse models, laying the groundwork for a gene-silencing approach in humans.
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Precision Medicine Approach: Antisense Oligonucleotides for Gene Silencing
Design and Rationale of Ulefnersen
Ulefnersen belongs to a class of molecules known as antisense oligonucleotides (ASOs), short strands of synthetic DNA designed to bind specifically to messenger RNA transcripts of a target gene—in this case, FUS—and trigger their degradation or prevent their translation into protein. By lowering both mutant and normal FUS protein levels, the therapy aims to halt the production of toxic aggregates while preserving sufficient normal FUS function, which preliminary studies indicated neurons can tolerate.
Expanded Access and First-in-Human Use
In 2019, Dr. Shneider secured approval from the U.S. Food and Drug Administration to administer ulefnersen under an expanded access—or compassionate use—protocol for Jaci Hermstad, a young woman from Iowa whose identical twin had succumbed to FUS-ALS. Over the next five years, at least 25 patients worldwide received intrathecal injections of ulefnersen, with 12 patients’ data compiled in the published case series.
Clinical Case Series: Unprecedented Recoveries and Biomarker Improvements
Profiles of Responders
Among the 12 treated patients, two stand out for exceptional clinical outcomes:
• Young Woman with Juvenile-Onset FUS-ALS: Since beginning ulefnersen in late 2020, she regained the ability to walk unaided and breathe without mechanical ventilation—functions previously lost to her relentless disease. At four years post-diagnosis, she has outlived every other known patient with her specific mutation.
• Mid-30s Presymptomatic Carrier: Identified through family screening and showing early electrodiagnostic signs of motor neuron dysfunction but no clinical weakness, this patient has remained symptom-free after three years of continuous treatment. Electromyography findings have actually improved over time, suggesting a preventive effect on disease onset.
Neurofilament Light Chain as a Biomarker
All patients experienced substantial reductions—up to 83%—in cerebrospinal fluid and blood levels of neurofilament light chain (NfL), a protein released during axonal injury and widely regarded as a reliable biomarker for neuronal damage in ALS and other neurodegenerative conditions. The rapid decline in NfL within six months of treatment initiation underscores the therapy’s potential to arrest ongoing neuronal degeneration.
Safety and Tolerability
Importantly, ulefnersen was well tolerated in all treated individuals, with no serious adverse events directly attributable to the drug. Mild, transient post–lumbar puncture headaches and back pain were the most commonly reported side effects, consistent with intrathecal administration procedures. No evidence of off-target toxicity or immunogenic reactions emerged during follow-up.
Expert Commentary: A Paradigm Shift for ALS Treatment
Dr. Neil Shneider’s Perspective
“These responses show that if we intervene early enough and target the right mechanism at the appropriate stage of disease, it’s possible not only to slow progression, but actually to reverse some functional losses,” says Dr. Shneider. “This is a wonderful example of precision medicine emerging from basic science insights into disease biology.”
Independent Experts’ Views
Dr. Merit Cudkowicz, Director of the Healey & AMG Center for ALS at Massachusetts General Hospital, remarks, “Seeing true motor function recovery in ALS is unprecedented. Although the sample is small and limited to FUS-mutant cases, these results validate ASO-driven gene silencing as a viable therapeutic strategy.” Dr. Timothy Miller, a neurologist and researcher at Washington University in St. Louis, adds, “The biomarker improvements are especially encouraging. If sustained in larger trials, this approach could redefine our expectations for ALS trial outcomes.”
Next Steps: Global Clinical Trial and Regulatory Pathway
Phase 3 Trial Underway
Bolstered by the remarkable early data, Ionis Pharmaceuticals has launched a randomized, placebo-controlled Phase 3 trial of ulefnersen in FUS-ALS patients across multiple countries. The trial aims to enroll 60 symptomatic individuals and assess the therapy’s efficacy on functional scales (ALSFRS-R), respiratory measures, survival, and biomarker endpoints over 12 months.
Regulatory Considerations
Given the severity and rarity of FUS-ALS, ulefnersen may qualify for accelerated regulatory pathways such as the FDA’s Breakthrough Therapy designation and Europe’s PRIME scheme, which facilitate expedited review for promising therapies addressing unmet medical needs. Company officials indicate that, pending positive Phase 3 results, they will seek conditional approval as early as 2026.
Broader Implications for ALS and Neurodegeneration
Applicability to Other ALS Subtypes
While ulefnersen’s mechanism is specific to FUS mutations, the success of ASO therapies in other genetic forms of ALS—such as SOD1 (tofersen) and C9orf72—suggests a growing arsenal of gene-targeted treatments. As genotyping becomes standard in ALS diagnosis, precision medicine approaches may extend to a substantial fraction of familial and even sporadic cases.
Lessons for Alzheimer’s and Huntington’s Diseases
The demonstration that early gene silencing can preserve or restore neuronal function carries implications beyond ALS. Neurodegenerative disorders marked by toxic protein accumulation—such as Huntington’s disease and certain forms of frontotemporal dementia—are also targets for ASO-based interventions. Positive outcomes in FUS-ALS further validate the broader platform of antisense therapeutics in neurology.
The Path Ahead: Challenges and Hope
Early Intervention and Biomarker Screening
A key lesson from the FUS-ALS cases is the importance of presymptomatic identification. Family members of ALS patients may benefit from genetic counseling and early biomarker screening to detect disease processes before irreversible neuronal loss occurs. Timely intervention could maximize therapeutic benefit, as suggested by the outstanding outcome in the presymptomatic carrier.
Access and Equity Considerations
While the rarity of FUS-ALS limits the immediate impact to a small patient population, the high cost and specialized delivery of ASO therapies pose challenges for global access. Stakeholders—pharmaceutical companies, insurers, and health systems—must collaborate to ensure equitable distribution and affordability once regulatory approvals are granted.
A New Chapter in ALS Research
The unprecedented recoveries seen with ulefnersen mark a watershed moment in the decades-long quest for ALS treatments. By transforming an aggressive, fatal form of ALS into a potentially manageable condition, this experimental therapy offers a beacon of hope to patients and researchers alike. As the Phase 3 trial progresses and the vision of effective disease-modifying and even restorative treatments comes into clearer focus, the era of accepting inevitable neurological decline may give way to a future where early genetic intervention can alter the course of neurodegeneration.
