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Updated: Apr 3, 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
Adverse effects of a SOD1-peptide immunotherapy on SOD1 G93A mouse slow model of amyotrophic lateral sclerosis
J Sábado1, A Casanovas1, H Rodrigo1
1Universitat de Lleida, Facultat de Medicina-IRBLLEIDA, Departament de Medicina Experimental, Unitat de Neurobiologia Cel·lular, Avda Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
Abstract:
Previous reports from our lab had shown that some anti-purinergic receptor P2X4 antibodies cross-reacted with misfolded forms of mutant Cu/Zn superoxide dismutase 1 (SOD1), linked to amyotrophic lateral sclerosis (ALS). Cross-reactivity could be caused by the abnormal exposure of an epitope located in the inner hydrophobic region of SOD1 that shared structural homology with the P2X4-immunizing peptide. We had previously raised antibodies against human SOD1 epitope mimicked by the P2X4 immunizing peptide. One of these antibodies, called AJ10, was able to recognize mutant/misfolded forms of ALS-linked mutant SOD1. Here, we used the AJ10 antigen as a vaccine to target neurotoxic species of mutant SOD1 in a slow mouse model of ALS. However, the obtained results showed no improvement in life span, disease onset or weight loss in treated animals; we observed an increased microglial neuroinflammatory response and high amounts of misfolded SOD1 accumulated within spinal cord neurons after AJ10 immunization. An increase of immunoglobulin G deposits was also found due to the treatment. Finally, a significantly worse clinical evolution was displayed by an impairment on motor function as a consequence of AJ10 peptide immunization.
Insights
Vaccinating mice with the AJ10 antigen, targeting misfolded SOD1 in ALS, unexpectedly worsened disease progression and motor function. This approach increased neuroinflammation and SOD1 accumulation, highlighting potential risks of targeting misfolded proteins in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Misfolded Cu/Zn superoxide dismutase 1 (SOD1) is linked to amyotrophic lateral sclerosis (ALS).
- Antibodies targeting misfolded SOD1 may offer therapeutic potential.
- Previous work identified cross-reactivity between anti-P2X4 antibodies and misfolded SOD1.
Purpose of the Study:
- To investigate the therapeutic efficacy of AJ10 antigen vaccination targeting misfolded SOD1 in a mouse model of ALS.
- To assess the impact of AJ10 immunization on disease onset, lifespan, and motor function.
Main Methods:
- Utilized a slow mouse model of ALS.
- Administered AJ10 antigen as a vaccine to target neurotoxic SOD1 species.
- Monitored lifespan, disease onset, weight loss, and motor function.
- Analyzed microglial neuroinflammatory response, SOD1 accumulation, and immunoglobulin G deposits.
Main Results:
- AJ10 immunization did not improve lifespan, disease onset, or weight loss in treated mice.
- Observed increased microglial neuroinflammation and accumulation of misfolded SOD1 within spinal cord neurons.
- Detected increased immunoglobulin G deposits post-treatment.
- AJ10 immunization led to a significantly worse clinical evolution, including impaired motor function.
Conclusions:
- Vaccination with the AJ10 antigen targeting misfolded SOD1 exacerbates neuroinflammation and worsens clinical outcomes in a mouse model of ALS.
- The strategy of immunizing against misfolded SOD1 using the AJ10 antigen is not beneficial and potentially detrimental for ALS progression.
- Further research is needed to understand the mechanisms behind the adverse effects and to develop safer therapeutic strategies for ALS targeting misfolded proteins.
