ALS THERAPY - TARGETS FOR THE FUTURE

There are four main hypotheses about the cause of ALS: excitotoxicity Linked to glutamate receptor overactivation; mutation of the superoxid e dismutase gene; production of autoantibodies to calcium channels; ne urofilament accumulation. The motoneuron degeneration characteristic o f ALS could be caused by any one or a combination of these mechanisms. Future therapeutic approaches should be based on these mechanisms and given in combination so that different levels of the degenerative pro cess are targeted. Protection against excitotoxicity could be achieved with a combination of pharmacologic agents having neuroprotective act ivity, such as antiglutamate agents (e.g., riluzole), N-methyl-D-aspar tate (NMDA) and non-NMDA antagonists, free-radical scavengers, calcium -channel blockers, and neurotrophic factors. Gene transfer is a possib le future approach when causative mutations are identified. Transfer o f genes encoding neuroprotective agents or genetically modified cells stably expressing these agents is another possible strategy.