Résumé :
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Amyotrophic Lateral Sclerosis (ALS) remains an intriguing neurodegenerative disorder and we do net yet understood its pathogenesis. The discovery of the Cu, Zn superoxyde dismutase gene (SOD1) mutation in 20% of familial cases dramatically modified the research perspectives in ALS. The mouse model of SOD1– related familial ALS has triggered research into the mechanisms that underlie ALS. Argument was that many downstream pathologic processes in SOD1- mediated motor neuron death most probably also have a role in sporadic ALS. This and other knowledge on neurodegeneration led to propose many trials in ALS of different compounds having putative beneficial effects mainly through anti-excitotoxic, anti-oxidant, neurotrophic and anti-apoptotic action. However, over the last 10 to 15 years, the number of negative trials has become impressive. These drugs were used orally, subcutaneously or by the subarachnoid route directly in the CSF. The number of ineffective clinical trials, with the exception of riluzole, and the linked disappointment beg some questions. Is the standard animal model, SOD1 mouse, relevant? The usual path of the unsuccessful agents is: in vitro demonstration of action on the hypothesised pathogenic pathway, significant improvement of the animal model, and failure in human clinical trial. Some preliminary assumptions are perhaps non-verified. The SOD1 mouse represents a model of SOD1- related familial ALS but is it relevant to sporadic ALS? A positive trial in the mouse is based on a presymptomatic initiation of treatment but is it relevant to the human trial in which the treatment is delivered a long time after the onset of the disease? Does pharmacokinetics used in mouse relevant to human studies? The clinical trial design in ALS has varied and remains clearly far to be perfect. Patients and clinicians would prefer to initiate ALS therapy as early as possible but there remain difficulties with absence of a specific diagnostic test and difficulties with accurate early diagnosis. Trial end points choice has been extensively discussed and each one has its own positive and negative arguments: time to death, quantified muscle testing with composite score of the whole body or restricted to one limb, forced vital capacity, functional rating scale such as ALSFRS-R. Some trial design utilized a lead-in period that allows calculating a pre-treatment rate of change for each individual participant and within-subject comparison to avoid the high inter-subject variability. Finally, during the last decade standards of care have also greatly changed and this has to be taken account in the evaluation of a drug benefit.
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