MINOCYCLINE IN 400 SUBJECTS WITH ALS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Amyotrophic lateral sclerosis leads to degeneration of the voluntary motor system and death on average in 3 years. The course is progressive with a decline in function with time. There is no cure or known treatment that significantly improves function. The prevalence is 4-6 cases per 100,000 with an incidence of 0.4 to 1.8 per 100,000. The majority of ALS cases are sporadic. However, 10-15% are inherited as an autosomal dominant trait known as familial ALS (FALS). Of these, 25% are associated with a defect in the gene encoding the enzyme copper-zinc superoxide dismutase (SOD1). After discovery of mutant SOD1 in FALS, a transgenic mouse model was developed using the same gene. The SOD1 FALS rodent model has become an important method of pathological study and therapeutic drug screening in ALS. The sporadic and familial forms of human ALS are clinically and pathologically similar. Minocycline was selected for this study because its effects may inhibit motor nerve degeneration at several points. It likely inhibits cell death pathways by preventing both pro-apoptotic and pro-inflammatory enzyme activation. It inhibits release of mitochondrial cytochrome c and inhibits p38 mitogen activated protein (MAP) kinase, thus reducing cyclical activation and production of caspase enzymes, microglia, cytokines and oxidative species. It slows deterioration in several models of neurodegeneration, including ALS. It has neuroprotective benefit in experimental ischemia, and it has proven efficacy in human inflammatory arthritis, separate from its antibiotic properties. Hypothesis: Neuronal death in ALS may include apoptosis. Minocycline has shown anti-apoptotic effects and has slowed the rate of progression in a transgenic mouse model of ALS. Specific Aim 1: Minocycline will slow the rate of progression in ALS by 15%. Specific Aim 2: Minocycline will be tolerated at 200 mg/BID.