No Benefit from Chronic Lithium Dosing in a Sibling-Matched, Gender Balanced, Investigator-Blinded Trial Using a Standard Mouse Model of Familial ALS

Abstract

BackgroundIn 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 FindingsSeeking 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/SignificanceRigorous survival study design that includes sibling matching, gender balancing, investigator blinding, and transgene copy number verification for each experimental subject minimized the likelihood of attaining a false positive therapeutic effect in this standard animal model of familial ALS. Results from this study do not support taking lithium carbonate into human clinical trials for ALS.

NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy

“…In this regard, a recent study did not identify any therapeutic benefit of chronic lithium treatment with respect to disease onset, progression of neurological symptoms, or survival duration in a mouse model (73). Interestingly, and in good agreement with our study, the study found evidence for early onset of low-grade neurological symptoms and signs of less-effective body weight maintenance (73). Regarding lithium clinical trials for AD (19,23,74), frequent extrapyramidal side effects were already detected in a pilot study (22), and a recent study of the feasibility and tolerability of lithium therapy in AD patients reports high rates of discontinuation due to the high incidence of lithium toxicity in the elderly (19).…”

“…Regarding the ongoing clinical trials of lithium for ALS (71), it will be of particular interest to see whether the potential observed in the initial study (70) is confirmed, given the well-known role of Fas signaling in mediating apoptotic death of ALS spinal motoneurons (72). In this regard, a recent study did not identify any therapeutic benefit of chronic lithium treatment with respect to disease onset, progression of neurological symptoms, or survival duration in a mouse model (73). Interestingly, and in good agreement with our study, the study found evidence for early onset of low-grade neurological symptoms and signs of less-effective body weight maintenance (73).…”

Preclinical research: Make mouse studies work

“…Concurrently, other groups attempted to reproduce the preclinical data and could not 12,13 . Although it is difficult to determine why the first study showed such a dramatic effect, its initial results are curious.…”

Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease

“…;DLK WT (black), n = 21 (with none being censored). Log-rank test (*P = 0.0085) for the whole model, with a significant DLK genotype effect (**P = 0.0028); sex effect (not significant To determine whether the protection of motor neurons after Dlk deletion would provide lasting functional benefit, we examined symptom progression and life span in an independent cohort of SOD1 (34), including the wire hang test, a measure of motor strength (Fig. 4H and fig.…”