Development of Immunization Approaches to Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons in the brain and spinal cord. Mutations in the gene encoding superoxide dismutase (SOD1) remain the major known genetic causes associated with ALS. Evidence suggests that the toxicity of SOD1 mutations is related to the abnormal misfolding and aggregation of mutant SOD1 proteins. The discovery of a secretion pathway for mutant SOD1 increased the possibility of using immunization approaches to reduce or neutralize the burden of toxic SOD1 species in the nervous system. Both active and passive immunization protocols were successful in delaying the onset of disease and mortality in transgenic mice expressing mutant SOD1. Owing to the potential adverse immune responses, immunization strategies need to be considered cautiously before being tested in human clinical trials. Critical issues for development of human immunotherapy will be discussed including the routes and methods of antibody delivery, the specificity of antibodies and immune responses, the penetration through the BBB and the time to start treatment. Prophylactic immunotherapy may become a conceivable approach for SOD1-linked ALS patients providing that the treatment is not overly invasive and can be implemented at reasonable cost. This article reviews how innate and adaptive immunity can affect the pathogenesis of ALS and how harnessing the immune system through immunization approaches might offer promising future therapeutic avenues.