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The key to selecting possible therapeutic agents lies in the understanding of a disease. To date the cause of ALS is not known, but several theories have been proposed and there is experimental evidence to support each theory. There may be interplay of one or more of these mechanisms that lead to nerve cell death in ALS. Furthermore, there may be genetic factors that are important to the predisposition to develop disease with the right provocation. The mechanisms of neuronal death in ALS that have been theorized include: defective glutamate metabolism, free radical injury, mitochondrial dysfunction, gene defects, programmed cell death (apoptosis), cytoskeletal protein defects (including neurofilament abnormalities), autoimmune dysfunction, and viral infections including retroviruses (HIV). These proposed causes of ALS have provided targets for drug therapies. Below we discuss what medications have been tried based on each of the theories.
While I have discussed the latest clinical trials in patients with ALS, one major advance in recent years has been the development of the transgenic mouse model of ALS. This mouse carries a mutated human SOD (Superoxide dismutase) gene. This mutated gene was identified in some patients with the hereditary form of ALS. The mice develop a motor system disease and die at around 125 days of age. This model has provided an animal model to study the disease and also to test new drugs. There have been over 50 agents now tried in the model. Its usefulness will be determined by the correlation of drug efficacy in the model compared to results in humans.
Recently a triple-drug cocktail consisting of riluzole, minocycline and nimodidpine was tested in the animal model. Minocycline, an antibiotic believed to inhibit apoptosis (cell suicide), has already been shown to extend survival in SOD1 mice by about three weeks when given alone and is being tested in ALS patients (see above under upcoming clinical trials). Nimodipine works by blocking the entry of calcium into neurons – thought by some ALS experts to be an early event in motor neuron death. Riluzole (Rilutek), the only FDA-approved drug for treating ALS, works by inhibiting the release of glutamate by brain cells. It extends life by just a few weeks in mice with the disease and by a few months in people with ALS. SOD1 mice given all three drugs when they were in the early stages of ALS lived about six weeks longer than untreated mice did. Since all three drugs have FDA approval for treating different diseases, the triple-drug cocktail could be fast-tracked into clinical trials.
While the animal model is an exciting advance for both use in clinical evaluation and basic research into mechanism, the average clinical trial in the animal takes 6-9 months. Therefore, there has been an increasing interest in the development of rapid throughput assays for new drugs that could predict clinical response in ALS by patients in days rather than months. This has led to a large effort coordinated by the National Institutes of Neurological Diseases and Stroke (NINDS) to find treatments for some of the most devastating neurological diseases, including ALS, Huntington's disease, Parkinson's, spinal muscular atrophy and spinal bulbar muscular atrophy. There are nearly 30 laboratories across the country – collectively known as the Neurodegeneration Drug Screening Consortium (NDSC) – using a variety of methods to test the effects of more than 1,000 chemicals, most of which are FDA-approved drugs. These methods involve the development of assays that are rapidly performed and test drug effects on possible pathologic mechanisms relevant to the various diseases. For instance, the assays for the toxicity of glutamate have been included since glutamate excitotoxicity may play a role in ALS. If a compound mitigates toxicity in an ALS-specific assay, this may predict a response in people with ALS. Furthermore, there are several ALS specific assays included in the screening and compounds that work in more than just one assay are even more promising. To date, across all of the laboratories involved in the screening program there were seven chemicals that were hits in two or more of the ALS-specific tests, indicating that they might work against key parts of the disease process. The next steps for development is to test the drugs that work in ALS specific tests in the transgenic mouse model. If the results are promising, these compounds can be rapidly taken to clinical trial as they are already FDA approved for other uses. In fact, the first trial of one of the "hits" was scheduled to start early in 2005 with a clinical trial of Ceftriaxone. This will be given intravenously and daily.