Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
The initiation of tofersen, a new specific antisense oligonucleotide (ASO) for SOD1 pathology, marked a significant turning point for SOD1-ALS patients. While clinical trials and early access program studies reported a significant reduction in plasma and cerebrospinal fluid (CSF) neurofilament levels, neuroinflammation following prolonged treatment was never assessed. In this multicenter study, we evaluated a cohort of 18 SOD1-ALS patients treated with tofersen, analyzing correlations between biomarkers of neurodegeneration/neuroinflammation and clinical variables indicative of disease progression. NfL, NfH, CHI3L1, and Serpina1 levels in serum and CSF were determined by semi-automated immunoassays (Ella™ technology). Generalized linear mixed models were employed to investigate longitudinal trends of these biomarkers. Our data highlighted a progressive decrease in CSF neurofilament levels during tofersen treatment (MR = 0.97, 95% CI 0.94-0.99, p = 0.006 and MR = 0.98, 95% CI 0.95-1.00, p = 0.076 for NfL and NfH in CSF, respectively). Conversely, CSF levels of SerpinA1 and CHI3L1 increased over time (MR = 1.12, 95% CI 1.08-1.16, p < 0.0001 and MR = 1.039, 95% CI 1.015-1.062, p = 0.001 for SerpinA1 and CHI3L1 in CSF, respectively), but these modifications were most apparent after six and twelve months of therapy, respectively. Disease progression rate did not correlate with these biomarker trends. We observed a significant decrease in neurofilament levels during Tofersen treatment, alongside an increase in neuroinflammatory markers, potentially linked to an immune response triggered by ASO treatment. Given the limited data on tofersen's long-term efficacy in ALS due to its recent introduction, identifying biomarkers that predict clinical outcomes such as diminished therapeutic response or adverse effects is crucial. These biomarkers may help to better understand the underlying pathomechanisms of ALS and tofersen's role in modulating disease progression.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961715 | PMC |
| http://dx.doi.org/10.1038/s41598-025-94984-1 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Genotype-specific interferon signatures in amyotrophic lateral sclerosis relate to disease severity.
Brain
September 2025
IRCSS Fondazione Santa Lucia, European Center for Brain Research (CERC), Rome 00143, Italy.
Innate immune signaling pathways are hyperactivated in the central nervous system (CNS) of patients with Amyotrophic Lateral Sclerosis (ALS), as well as in preclinical models with diverse causative backgrounds including TDP-43, SOD1, and C9orf72 mutations. This raises an important question of whether these pathways are key pathogenic features of the disease, and whether therapeutic amelioration could be beneficial. Here, we systematically profile Type-I interferon (IFN)-stimulated gene (ISG) expression signatures using a non-biased approach in CNS tissue from a cohort of 36 individuals with ALS, including sporadic ALS (sALS; n=18), genetic ALS caused by (i) a C9orf72 hexanucleotide repeat expansion (C9-ALS; n=11), and (ii) a SOD1 mutation (SOD1-ALS; n=5), alongside age- and sex-matched individuals who died of a non-neurological cause (n=12).
View Article and Find Full Text PDFTargeting Amyotrophic Lateral Sclerosis with Gene Therapy: From Silencing Genes to Enhancing Neuroprotection.
Hum Gene Ther
September 2025
Institut de Neurociències (INc), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
Gene therapy is emerging as a transformative approach for treating amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disease. While gene replacement has shown a groundbreaking success in spinal muscular atrophy, the complexity of ALS-due to frequent gain-of-function mutations and a heterogeneous etiology-presents significant challenges. Importantly, approximately 90% of ALS cases are sporadic, with unknown genetic mutation, further complicating patient stratification and therapeutic targeting.
View Article and Find Full Text PDFCardiac Troponin T in Tofersen-Treated SOD1 ALS Patients: Beginning to Resolve the Catch-22 of Identifying Treatment Responsive Biomarkers in ALS Drug Development.
Muscle Nerve
August 2025
Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.
Antisense oligonucleotide therapy in amyotrophic lateral sclerosis.
Curr Opin Neurol
October 2025
Sheffield Institute for Translational Neuroscience, the University of Sheffield.
Purpose Of Review: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with few treatment options available. The approval of tofersen, an antisense oligonucleotide, for SOD1 -ALS by the FDA and EMA may herald a new era of treatment in these patients.
Recent Findings: So far, trials against the most common genetic form of ALS, C9orf72 , have been unsuccessful, but new preclinical data may show a promising new direction to take.
Objective: Tofersen is the first effective and approved therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS [SOD1-ALS]). Following treatment with tofersen, neurofilament levels in patients' cerebrospinal fluid (CSF) and serum seem to respond earlier than clinical parameters. This evidence prompted us to hypothesize that this novel treatment could provide an opportunity to identify additional biomarkers responsive to therapy in SOD1-ALS.
View Article and Find Full Text PDF