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Updated: Apr 28, 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
CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis
Matthew C Evans, Pieter J Gaillard, Marco de Boer
1Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. daniel.anthony@pharm.ox.ac.uk.
Background:
Hallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1G93A). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss. SOD1G93A mice were treated with saline, free methylprednisolone (MP, 10 mg/kg/week) or glutathione PEGylated liposomal MP (2B3-201, 10 mg/kg/week) and compared to saline treated wild-type animals. Animals were treated weekly with intravenous injections for 9 weeks from 60 days of age. Weights and motor performance were monitored during this period. At the end of the experimental period (116 days) mice were imaged using T2-weighted MRI for brainstem pathology; brain and spinal cord tissue were then collected for histological analysis.
Results:
All SOD1G93A groups showed a significant decrease in motor performance, compared to baseline, from ~100 days. SOD1G93A animals showed a significant increase in signal intensity on T2 weighted MR images, which may reflect the combination of neuronal vacuolation and glial activation in these motor nuclei. Treatment with 2B3-201, but not free MP, significantly reduced T2 hyperintensity observed in SOD1G93A mice. Compared to saline-treated and free-MP-treated SOD1G93A mice, those animals given 2B3-201 displayed significantly improved histopathological outcomes in brainstem motor nuclei, which included reduced gliosis and neuronal loss.
Conclusions:
In contrast to previous reports that employed free steroid preparations, CNS-targeted anti-inflammatory agent 2B3-201 (liposomal methylprednisolone) has therapeutic potential, reducing brainstem pathology in the SOD1G93A mouse model of ALS. 2B3-201 reduced neuronal loss and vacuolation in brainstem nuclei, and reduced activation preferentially in astrocytes compared with microglia. These data also suggest that other previously ineffective therapies could be of therapeutic value if delivered specifically to the CNS.
Insights
A novel liposomal glucocorticoid, 2B3-201, effectively reduced central nervous system (CNS) inflammation and motor neuron loss in an amyotrophic lateral sclerosis (ALS) mouse model. This targeted delivery improved brainstem pathology, offering potential for previously ineffective therapies.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Central nervous system (CNS) inflammation, marked by microglial and astrocyte activation, is a key feature in amyotrophic lateral sclerosis (ALS).
- Non-targeted glucocorticoid treatments have shown limited efficacy in altering ALS disease progression, potentially due to poor CNS delivery.
- This study investigated the potential of a CNS-targeted, liposomal encapsulated glucocorticoid to mitigate CNS inflammation and motor neuron degeneration in an ALS mouse model.
Purpose of the Study:
- To evaluate the efficacy of a novel CNS-targeted liposomal methylprednisolone (2B3-201) in reducing neuroinflammation and motor neuron loss in the SOD1G93A mouse model of ALS.
- To compare the therapeutic effects of liposomal methylprednisolone with free methylprednisolone and saline treatment.
- To assess the impact of 2B3-201 on brainstem pathology, including glial activation and neuronal survival.
Main Methods:
- SOD1G93A mice were administered weekly intravenous injections of saline, free methylprednisolone (MP), or glutathione PEGylated liposomal MP (2B3-201) for nine weeks, starting at 60 days of age.
- Motor performance and body weight were monitored throughout the treatment period.
- At the study's conclusion (116 days), T2-weighted MRI was used to assess brainstem pathology, followed by histological analysis of brain and spinal cord tissues.
Main Results:
- All SOD1G93A mice exhibited motor performance decline from approximately 100 days of age.
- T2-weighted MRI revealed increased signal intensity in SOD1G93A mice, indicative of neuronal vacuolation and glial activation.
- Treatment with 2B3-201, but not free MP, significantly reduced this T2 hyperintensity and improved histopathological outcomes, including reduced gliosis and neuronal loss in brainstem motor nuclei.
Conclusions:
- CNS-targeted liposomal methylprednisolone (2B3-201) demonstrates therapeutic potential in the SOD1G93A mouse model of ALS by reducing brainstem pathology.
- 2B3-201 effectively mitigated neuronal loss and vacuolation in brainstem nuclei, with a notable reduction in astrocyte activation compared to microglia.
- These findings suggest that targeted CNS delivery could enhance the therapeutic efficacy of agents previously found ineffective in ALS treatment.
