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Blood SOD1 Activity in ALS Patients Receiving Tofersen Treatment
Katharina Goehring1, Enya Abler1, Jakub Vavra1
1Department of Neurology, Ulm University Hospital, Ulm, Germany.
Annals of Neurology
|August 12, 2026
Summary
Tofersen treatment for SOD1-related ALS does not affect SOD1 activity, which is already reduced in patients before treatment. This finding suggests tofersen’s benefits are independent of SOD1 activity levels.
Area of Science:
- Neurology
- Genetics
- Biochemistry
Background:
- Tofersen is a disease-modifying drug for SOD1-related amyotrophic lateral sclerosis (ALS).
- Its approval was based on reducing SOD1 protein and neurofilament levels.
- The impact of tofersen on SOD1 activity remains unclear and is clinically significant due to potential deleterious effects of reduced activity.
Purpose of the Study:
- To investigate the effect of tofersen on SOD1 activity in patients with SOD1-related ALS.
- To determine if SOD1 activity is altered in different ALS subtypes and asymptomatic carriers.
- To assess the clinical relevance of SOD1 activity in the context of tofersen treatment.
Main Methods:
- SOD1 activity was measured in blood samples from discovery (n=120) and validation (n=208) cohorts.
- Cohorts included controls, sporadic ALS (sALS), C9orf72 mutation carriers (c9ALS), asymptomatic SOD1 carriers (SOD1-asym), and symptomatic SOD1 mutation carriers (SOD1-ALS).
- SOD1 activity was also characterized in 18 patients undergoing tofersen treatment.
Main Results:
- SOD1 activity was significantly lower in SOD1-asym and SOD1-ALS patients compared to controls, c9ALS, and sALS patients (p < 0.0001).
- Lower SOD1 activity correlated with deleterious SOD1 variants.
- During tofersen treatment, neurofilament and SOD1 protein levels decreased, while SOD1 activity remained stable.
Conclusions:
- Tofersen's therapeutic effect in SOD1-ALS is independent of SOD1 activity.
- Reduced SOD1 activity is specific to SOD1-ALS, present pre-symptomatically, and mutation-dependent.
- Further research is needed to evaluate tofersen's effect on cerebrospinal fluid (CSF) SOD1 activity.
