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Anti-SOD1 Immunization Delays Onset, Increases Lifespan in ALS Mice

July 3, 2012

Anti-SOD1 Immunization Delays Onset, Increases Lifespan in ALS Mice

Immunizing ALS mice against the mutant SOD1 protein delays disease onset and increases lifespan, according to research funded by The ALS Association and published this week in Journal of Neuroscience. “This study supports previous data demonstrating the potential of immunization as a treatment strategy,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D., “and furthermore describes the exact binding domain of the antibody on the mutant protein.” The study, led by Janice Robertson, Ph.D. at the University of Toronto, Canada, provides crucial insight into the mechanism through which mutant SOD1 causes disease.

Janice
Janice Robertson

Previous research has shown that immunization was possible and could provide protection in ALS mice, but the precise target on the surface of the SOD1 protein was unknown. In this study, the authors used an antibody designed to bind to the surface linking two SOD1 molecules (monomers) into a single protein (dimer). Normally, that surface is hidden between the two monomers. A feature of most, if not all, SOD1 mutations is that the linking surface is exposed. It is thought that this may increase the likelihood that SOD1 will aggregate into protein clumps, and those aggregates are thought to be toxic to motor neurons or other components of the nervous system. When antibody binds to this surface, it is a signal for the body’s immune system to clear the protein, reducing the likelihood of aggregation.

In this study, mice were injected with a short protein chain (peptide) similar to the linking surface, causing the immune system to make antibodies to it. (This injection strategy is similar to the immunization process used for polio and other infectious diseases.) Injections occurred weekly from 6 weeks to 5 months of age. Immunization delayed disease onset by about 26 days and lifespan by about 40 days in a less severe mouse model; in a more severe model, benefits were less. Treatment reduced accumulation of misfolded and aggregated protein in the spinal cord and induced a less inflammatory and more protective immune response.

“We are optimistic that now we have established monomer/misfolded SOD1 as a clear therapeutic target for ALS, the immunotherapy approach we describe here is only the first step to accelerating the pace toward providing an effective treatment for patients,” commented Dr. Robertson. “In addition to this approach, we are searching for small molecules that will ameliorate the toxicity of monomer/misfolded SOD1 in vivo". Because misfolded SOD1 may also occur in sporadic ALS, it is possible that immunization may also benefit forms of the disease not caused by mutation of SOD1.

Liu HN, Tjostheim S, DaSilva K Taylor D, Zhao B, Rakhit R, Brown M, Chakrabartty A, McLaurin J, Robertson J. Targeting of Monomer/Misfolded SOD1 as a Therapeutic Strategy for Amyotrophic Lateral Sclerosis. Journal of Neuroscience 2012; 32(26):8791–8799

>> For this month's journal news click here.

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