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      Lost in translation: treatment trials in the SOD1 mouse and in human ALS.

      Neurobiology of Disease
      Amyotrophic Lateral Sclerosis, drug therapy, genetics, Animals, Disease Models, Animal, Humans, Mice, Publication Bias, Research Design, Sex Characteristics, Superoxide Dismutase, Survival Analysis

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          Abstract

          Therapeutic success in the superoxide dismutase (SOD1) mouse model of amyotrophic lateral sclerosis (ALS) has not translated into effective therapy for human ALS, calling into question the utility of such preclinical data for identifying therapeutic agents that are worthy of further study in humans. This random effects meta-analysis of treatment trials in the superoxide dismutase (SOD1) mouse was undertaken in order to explore possible reasons for this failure of translational research and to identify potential pharmacological interventions that might be used in either a preventative or therapeutic trial in familial ALS. Among studies in which treatment was initiated presymptomatically, the weighted mean differences (WMDs) comparing the active treatment to control treated animals were 12 days (onset), 13 days (survival) and 5 days (survival interval). Among studies in which treatment was initiated at the time of symptom onset, the WMDs were 15 days (survival) and 8 days (survival interval). Subgroup analysis suggests that drugs such as minocycline and Cox-2 inhibitors with an anti-inflammatory mechanism of action, and anti-oxidative agents such as creatine or the manganese porphyrin AEOL-10150, appear to be the most promising for preventative and therapeutic trials respectively in patients with familial ALS. These conclusions should be tempered by the methodological limitations of the relevant literature.

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