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Updated: May 16, 2026
Lumbar Intrathecal Injection of SOD1-ASOs for Precise CNS Targeting and Predictive Efficacy in Human SOD1-G93A ALS Mice
Published on: February 24, 2026
SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy
Leah Winer1, Dushyanth Srinivasan, Seung Chun
1Department of Neurology, Washington University, St Louis, Missouri 63110, USA.
Background:
Therapies designed to decrease the level of SOD1 are currently in a clinical trial for patients with superoxide dismutase (SOD1)-linked familial amyotrophic lateral sclerosis (ALS).
Objective:
To determine whether the SOD1 protein in cerebral spinal fluid (CSF) may be a pharmacodynamic marker for antisense oligonucleotide therapy and a disease marker for ALS.
Design:
Antisense oligonucleotides targeting human SOD1 were administered to rats expressing SOD1G93A. The human SOD1 protein levels were measured in the rats' brain and CSF samples. In human CSF samples, the following proteins were measured: SOD1, tau, phosphorylated tau, VILIP-1, and YKL-40.
Participants:
Ninety-three participants with ALS, 88 healthy controls, and 89 controls with a neurological disease (55 with dementia of the Alzheimer type, 19 with multiple sclerosis, and 15 with peripheral neuropathy).
Results:
Antisense oligonucleotide-treated SOD1G93A rats had decreased human SOD1 messenger RNA levels (mean [SD] decrease of 69% [4%]) and decreased protein levels (mean [SD] decrease of 48% [14%]) in the brain. The rats' CSF samples showed a similar decrease in hSOD1 levels (mean [SD] decrease of 42% [14%]). In human CSF samples, the SOD1 levels varied a mean (SD) 7.1% (5.7%) after additional measurements, separated by months, were performed. The CSF SOD1 levels were higher in the participants with ALS (mean [SE] level, 172 [8] ng/mL; P<.05) and the controls with a neurological disease (mean [SE] level, 172 [6] ng/mL; P<.05) than in the healthy controls (mean [SE] level, 134 [4] ng/mL). Elevated CSF SOD1 levels did not correlate with disease characteristics in participants with ALS or controls with dementia of the Alzheimer type, but they did correlate with tau, phosphorylated tau, VILIP-1 and YKL-40 levels in controls with dementia of the Alzheimer type.
Conclusions:
SOD1 in CSF may be an excellent pharmacodynamic marker for SOD1-lowering therapies because antisense oligonucleotide therapy lowers protein levels in the rat brain and rat CSF samples and because SOD1 levels in CSF samples from humans are stable over time.
Insights
Superoxide dismutase (SOD1) in cerebrospinal fluid (CSF) shows promise as a biomarker for amyotrophic lateral sclerosis (ALS) and a marker for SOD1-lowering therapies, as demonstrated in rat models and human studies.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Familial amyotrophic lateral sclerosis (ALS) linked to superoxide dismutase (SOD1) mutations is a target for SOD1-lowering therapies currently in clinical trials.
- Investigating biomarkers is crucial for monitoring therapeutic efficacy and disease progression in neurodegenerative disorders.
Purpose of the Study:
- To evaluate the potential of cerebrospinal fluid (CSF) SOD1 protein as a pharmacodynamic marker for antisense oligonucleotide (ASO) therapy.
- To determine if CSF SOD1 serves as a disease marker for ALS.
Main Methods:
- Antisense oligonucleotides targeting SOD1 were administered to SOD1G93A rats, with SOD1 levels measured in brain and CSF.
- Human CSF samples from participants with ALS, healthy controls, and neurological disease controls were analyzed for SOD1, tau, phosphorylated tau, VILIP-1, and YKL-40 levels.
Main Results:
- ASO treatment in rats significantly reduced SOD1 mRNA and protein levels in both brain and CSF.
- Human CSF SOD1 levels were found to be stable over time.
- CSF SOD1 levels were elevated in patients with ALS and neurological disease controls compared to healthy controls.
Conclusions:
- CSF SOD1 is a potential pharmacodynamic marker for SOD1-lowering therapies due to its reduction following ASO treatment in rats.
- Stable SOD1 levels in human CSF suggest its utility as a reliable biomarker for ALS and therapeutic monitoring.
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