Amyotrophic lateral sclerosis (ALS; also see 6.08 Neurodegeneration) ALS is a neurodegenerative disease characterized by selective loss of spinal cord and cranial motor neurons. Patients are devastated by progressive muscle weakness and atrophy, and die of respiratory failure. Over 90% of ALS cases are sporadic; of the familial cases of ALS, a fraction is caused by mutations in the gene for the free-radical scavenger superoxide dismutase (SOD)-1. It has been hypothesized that sporadic ALS is an autoimmune disease.
The evidence for this hypothesis comes from animal and human studies. In SOD-1 mutant mice, the onset of disease is preceded by an inflammatory response, involving microglial activation and astrocytosis. In addition, minocycline, a tetracycline antibiotic with anti-inflammatory effects (Figure 1 and Table 2), extends survival in mouse models of ALS. In ALS patients, spinal cord fluid shows elevated levels of proteins involved in inflammation. Also intriguing is a controlled study noting morphological evidence of motor neuron degeneration in mice injected with IgG purified from ALS patients.20
The strongest evidence against the ALS autoimmune hypothesis derives from the fact that immunosuppression and PE fail to alter disease progression, the most recent failure being with the cyclooxygenase 2 inhibitor, rofecoxib, an antiinflammatory drug commonly used to treat arthritis, including rheumatoid arthritis (RA). While rofecoxib improved the life span of mutant SOD-1 mice, in clinical trials it had no effect on ALS progression.
There are currently three clinical trials addressing the ALS autoimmune hypothesis: two Phase II trials evaluating thalidomide, which has anticytokine, tumor necrosis factor (TNF)-a-inhibitory activity - as well as antiangiogenic properties and a third trial, Phase III, examining minocycline (see Figure 1 and Table 2).
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