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Neurofilament light-chain response during therapy with antisense oligonucleotide tofersen in SOD1-related ALS:
Thomas Meyer1,2, Peggy Schumann2, Patrick Weydt3,4
1Department of Neurology, Center for ALS and Other Motor Neuron Disorders, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
Introduction/Aims:
In amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1-ALS), the antisense oligonucleotide tofersen had been investigated in a phase III study (VALOR) and subsequently introduced in an expanded access program. In this study we assess neurofilament light chain (NfL) before and during tofersen treatment.
Methods:
In six SOD1-ALS patients treated with tofersen at three specialized ALS centers in Germany, NfL in cerebrospinal fluid (CSF-NfL) and/or serum (sNfL) were investigated using the ALS Functional Rating Scale Revised (ALSFRS-R) and ALS progression rate (ALS-PR), defined by monthly decline of ALSFRS-R.
Results:
Three of the six SOD1-ALS patients reported a negative family history. Three patients harbored a homozygous c.272A > C, p.(Asp91Ala) mutation. These and two other patients showed slower progressing ALS (defined by ALS-PR <0.9), whereas one patient demonstrated rapidly progressing ALS (ALS-PR = 2.66). Mean treatment duration was 6.5 (range 5 to 8) months. In all patients, NfL decreased (mean CSF-NfL: -66%, range -52% to -86%; mean sNfL: -62%, range -36% to -84%). sNfL after 5 months of tofersen treatment was significantly reduced compared with the nearest pretreatment measurement (P = .017). ALS-PR decreased in two patients, whereas no changes in ALSFRS-R were observed in four participants who had very low ALS-PR or ALSFRS-R values before treatment.
Discussion:
In this case series, the significant NfL decline after tofersen treatment confirmed its value as response biomarker in an expanded clinical spectrum of SOD1-ALS. Given the previously reported strong correlation between sNfL and ALS progression, the NfL treatment response supports the notion of tofersen having disease-modifying activity.
Insights
Tofersen treatment significantly reduced neurofilament light chain (NfL) levels in patients with amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations. This NfL decline suggests tofersen may have disease-modifying effects in SOD1-ALS.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease.
- Mutations in the superoxide dismutase 1 (SOD1) gene cause a subset of ALS cases (SOD1-ALS).
- Tofersen, an antisense oligonucleotide, targets SOD1 mRNA to reduce toxic protein levels.
Purpose of the Study:
- To assess the effect of tofersen treatment on neurofilament light chain (NfL) levels in patients with SOD1-ALS.
- To evaluate NfL as a biomarker for treatment response in SOD1-ALS.
Main Methods:
- Six patients with SOD1-ALS received tofersen treatment.
- Cerebrospinal fluid (CSF-NfL) and serum (sNfL) levels were measured before and during treatment.
- ALS Functional Rating Scale Revised (ALSFRS-R) and ALS progression rate (ALS-PR) were also assessed.
Main Results:
- All patients showed a significant decrease in NfL levels (mean CSF-NfL: -66%, mean sNfL: -62%).
- Serum NfL levels were significantly reduced after 5 months of tofersen treatment (P=.017).
- ALS-PR decreased in two patients; ALSFRS-R showed no change in four patients with slow progression or low baseline scores.
Conclusions:
- The significant decline in NfL levels confirms its utility as a response biomarker in SOD1-ALS.
- The observed NfL reduction supports the potential disease-modifying activity of tofersen in SOD1-ALS.
- Further research is warranted to fully elucidate tofersen's efficacy and long-term impact.
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