Abstract
Objective: To determine the safety of L-serine as a treatment for ALS
Background: β-N-methylamino-L-alanine (BMAA) has been linked to Guam ALS/PDC, and shown to produce neurodegeneration in vitro and in vivo (Drosophila, mice, rats, primates). BMAA misincorporation into neuroproteins via L-seryl tRNA synthetase produces protein misfolding, which is inhibited by L-serine.
Design/Methods: A 6-month randomized Phase I trial of oral L-serine was performed in 20 ALS patients (0.5 g to 15 g twice daily). Entry criteria included ALSFRS-R score >25 and FVC >60% predicted. Safety and tolerability were assessed, including by comparing the rate of deterioration of ALSFRS-R score and FVC with 430 matched placebo control patients from 5 previous trials.
Results: Two patients withdrew because of gastro-intestinal side effects (bloating, 15 g twice daily for 4 months; nausea and loss of appetite, 7.5 g twice daily for one month). One other patient had loss of appetite (2.5 g twice daily) but completed the trial. Three patients died during the study, which was about the expected number. The ALSFRS-R in the L-serine-treated patients showed a dose-related decrease in the rate of progression (linear mixed effects model corrected for initial FVC and symptom duration, 34% reduction in slope, p=0.044). The rate of decline of FVC in the L-serine patients did not differ from that in the historical placebo controls. L-serine concentration in the CSF showed a ~4-fold rise at the end of the study in the highest dose group. BMAA was not detected in the blood or CSF, confirming the findings of others.
Conclusions: L-serine in doses up to 15 g twice daily appears to be safe in patients with ALS. Exploratory studies of efficacy showed no evidence that L-serine caused disease acceleration and suggested the possibility of a dose-related slowing of disease progression. A Phase II trial is in development.
Study Supported by: Brain Chemistry Labs, Institute for Ethnomedicine, Jackson Hole, WY
Disclosure: Dr. Bradley has nothing to disclose. Dr. moore has nothing to disclose. Dr. Miller has received personal compensation for activities with Cytokinetics and Synapse Pharmaceuticals. Dr. Saperstein has received personal compensation for activities with Grifols, Baxter, NuFactor, and Corintian as a speaker, consultant, and partial owner. Dr. Forshew has received personal compensation for activities with Questcor Pharmaceuticals, Inc. and Asubio Pharmaceuticals.
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