no benefit from chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using a standard mouse model of familial als没有受益于慢性锂sibling-matched剂量,性别平衡,investigator-blinded试验使用标准的家族性肌萎缩性侧索硬化症小鼠模型.pdfVIP

No Benefit from Chronic Lithium Dosing in a Sibling- Matched, Gender Balanced, Investigator-Blinded Trial Using a Standard Mouse Model of Familial ALS Alan Gill*, Joshua Kidd, Fernando Vieira, Kenneth Thompson, Steven Perrin ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America Abstract Background: In any animal model of human disease a positive control therapy that demonstrates efficacy in both the animal model and the human disease can validate the application of that animal model to the discovery of new therapeutics. Such a therapy has recently been reported by Fornai et al. using chronic lithium carbonate treatment and showing therapeutic efficacy in both the high-copy SOD1G93A mouse model of familial amyotrophic lateral sclerosis (ALS), and in human ALS patients. Methodology/Principal Findings: Seeking to verify this positive control therapy, we tested chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using the high-copy (average 23 copies) SOD1G93A mouse (n = 27–28/group). Lithium-treated mice received single daily 36.9 mg/kg i.p. injections from 50 days of age through death. This dose delivered 1 mEq/kg (6.94 mg/kg/day lithium ions). Neurological disease severity score and body weight were determined daily during the dosing period. Age at onset of definitive disease and survival duration were recorded. Summary measures from individual body weight changes and neurological score progression, age at disease onset, and age at death were compared using Kaplan-Meier and Cox proportional hazards analysis. Our study did not show lithium efficacy by any measure. Conclusions/Significance: Rigorous survival study design that includes sibling matching, gender balancing, investigator