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Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis

Author:
Urushitani, Makoto, Ezzi, Samer Abou, Julien, Jean-Pierre
Source:
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.7 pp. 2495-2500
ISSN:
0027-8424
Subject:
Western blotting, amyotrophic lateral sclerosis, animal models, antigens, gene overexpression, longevity, mice, monoclonal antibodies, mutants, mutation, neurotoxicity, spinal cord, superoxide dismutase, vaccination
Abstract:
There is emerging evidence for the existence of secretory pathways for superoxide dismutase (SOD1) mutants linked to amyotrophic lateral sclerosis (ALS) and for neurotoxicity of extracellular mutant SOD1. This evidence led us to test immunization protocols aiming to reduce the burden of extracellular SOD1 mutants in nervous tissue of mice models of ALS, by using bacterially purified recombinant SOD1 mutant protein as an immunogen. First, a vaccination was tested on a G37R SOD1 mouse strain with late-onset disease exhibiting levels of mutant SOD1 protein at 4-fold higher than normal SOD1 levels. Repeated injections of adjuvant/SOD1 mutant with a final booster injection before symptoms at 6 months of age were effective in delaying disease onset and extending the life span of G37R SOD1 mice by >4 weeks. Western blot analysis with a monoclonal antibody specific to mutant SOD1 forms provided evidence of clearance of SOD1 species in the spinal cord of vaccinated G37R SOD1 mice. In contrast, this vaccination approach failed to confer significant protection in G93A SOD1 mice with extreme overexpression of mutant SOD1. Nonetheless, a passive immunization through intraventricular infusion of purified anti-human SOD1 antibody with osmotic minipump succeeded in alleviating disease symptoms and prolonging the life span of G93A SOD1 mice. From these results, we propose that immunization strategies should be considered as potential avenues for treatment of familial ALS caused by SOD1 mutations.
Agid:
2351631