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

Neurobiol Dis. 2007 Apr;26(1):1-13. doi: 10.1016/j.nbd.2006.12.015. Epub 2007 Jan 3.

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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Disease Models, Animal
  • Humans
  • Mice
  • Publication Bias
  • Research Design
  • Sex Characteristics
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase-1
  • Survival Analysis

Substances

  • SOD1 protein, human
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1