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Updated: Apr 21, 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
Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice
Oleg Butovsky1, Mark P Jedrychowski, Ron Cialic
1Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02112.
Objective:
To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).
Methods:
NanoString microRNA, microglia and immune gene profiles, protein mass spectrometry, and RNA-seq analyses were measured in spinal cord microglia, splenic monocytes, and spinal cord tissue from SOD1 mice and in spinal cord tissue of familial and sporadic ALS. miR-155 was targeted by genetic ablation or by peripheral or centrally administered anti-miR-155 inhibitor in SOD1 mice.
Results:
In SOD1 mice, we found loss of the molecular signature that characterizes homeostatic microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, and Mafb, and the upstream regulators Csf1r, Tgfb1, and Tgfbr1, which are essential for microglial survival. Microglia biological functions were suppressed including phagocytosis. Genetic ablation of miR-155 increased survival in SOD1 mice by 51 days in females and 27 days in males and restored the abnormal microglia and monocyte molecular signatures. Disease severity in SOD1 males was associated with early upregulation of inflammatory genes, including Apoe in microglia. Treatment of adult microglia with apolipoprotein E suppressed the M0-homeostatic unique microglia signature and induced an M1-like phenotype. miR-155 expression was increased in the spinal cord of both familial and sporadic ALS. Dysregulated proteins that we identified in human ALS spinal cord were restored in SOD1(G93A) /miR-155(-/-) mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes, and peripheral anti-miR-155 treatment prolonged survival.
Interpretation:
We found overexpression of miR-155 in the SOD1 mouse and in both sporadic and familial human ALS. Targeting miR-155 in SOD1 mice restores dysfunctional microglia and ameliorates disease. These findings identify miR-155 as a therapeutic target for the treatment of ALS.
Insights
Overexpression of miR-155 is linked to amyotrophic lateral sclerosis (ALS) in mice and humans. Targeting miR-155 in SOD1 mice improves microglia function and ameliorates disease, identifying it as a potential therapeutic target for ALS.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complex pathophysiology.
- Microglia, the immune cells of the central nervous system, play a critical role in ALS pathogenesis.
- MicroRNA-155 (miR-155) has been implicated in immune responses and inflammation, but its specific role in ALS remains to be fully elucidated.
Purpose of the Study:
- To investigate the role of miR-155 in the SOD1 mouse model of ALS and in human sporadic and familial ALS.
- To determine if targeting miR-155 can ameliorate disease phenotypes in the SOD1 mouse model.
Main Methods:
- Utilized NanoString microRNA, immune gene profiling, mass spectrometry, and RNA-seq analyses in spinal cord microglia, splenic monocytes, and spinal cord tissue from SOD1 mice and human ALS patients.
- Employed genetic ablation of miR-155 and administration of anti-miR-155 inhibitors (centrally and peripherally) in SOD1 mice.
Main Results:
- SOD1 mice exhibited increased miR-155 expression and a loss of homeostatic microglia signatures, with suppressed microglial functions.
- Genetic ablation of miR-155 in SOD1 mice significantly increased survival and restored microglial and monocyte molecular signatures.
- miR-155 was upregulated in the spinal cords of both familial and sporadic human ALS patients, and targeting miR-155 in mice improved disease phenotypes and prolonged survival.
Conclusions:
- Overexpression of miR-155 is a conserved feature in both the SOD1 mouse model and human ALS (sporadic and familial).
- Targeting miR-155 effectively restores dysfunctional microglia and ameliorates disease progression in the SOD1 mouse model.
- These findings highlight miR-155 as a promising therapeutic target for the treatment of amyotrophic lateral sclerosis.
