Studies of Environmental Risk Factors in Amyotrophic Lateral Sclerosis (ALS) and a Phase I Clinical Trial of l-Serine

Walter G Bradley, R. X. Miller, T. D. Levine, E. W. Stommel, P. A. Cox

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 produces protein misfolding and is inhibited by l-serine. Case-control studies in Northern New England indicate that living near to water-bodies with cyanobacterial blooms increases the risk of developing amyotrophic lateral sclerosis (ALS). The distribution of addresses of ALS cases in New Hampshire, Vermont, and Florida was compared to that of controls. Areas of statistically significantly increased numbers of ALS cases were examined for sources of environmental toxins. A phase I trial of oral l-serine was performed in 20 ALS patients (0.5 to 15 g twice daily). Safety and tolerability were assessed by comparing the rate of deterioration with 430 matched placebo controls. The distribution of residential addresses of ALS cases in New England and Florida revealed many areas where the age- and gender-adjusted frequency of ALS was greater than expected (P < 0.01). GIS studies of these “hot spots” in relation to sources of environmental pollutants, like cyanobacterial blooms, Superfund and Brownfield sites, and landfills, are ongoing. In the phase I trial of l-serine, two patients withdrew from because of gastrointestinal side effects. 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 (34% reduction in slope, P = 0.044). The non-random distribution of addresses of ALS patients suggests that residential exposure to environmental pollutants may play an important role in the etiology of ALS. l-Serine in doses up to 15 g twice daily appears to be safe in patients with ALS. Exploratory studies of efficacy suggested that l-serine might slow disease progression. A phase II trial is planned.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalNeurotoxicity Research
DOIs
StateAccepted/In press - May 19 2017

Fingerprint

Clinical Trials, Phase I
Amyotrophic Lateral Sclerosis
Serine
Environmental Pollutants
New England
Land fill
Alanine
Geographic information systems
Guam
Deterioration
Rats
Waste Disposal Facilities
Body Water
Water
Primates
Drosophila
Disease Progression
Case-Control Studies
Placebos
Proteins

Keywords

  • Amyotrophic lateral sclerosis
  • BMAA
  • Cyanobacteria
  • Environmental epidemiology
  • l-Serine
  • Treatment

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

Studies of Environmental Risk Factors in Amyotrophic Lateral Sclerosis (ALS) and a Phase I Clinical Trial of l-Serine. / Bradley, Walter G; Miller, R. X.; Levine, T. D.; Stommel, E. W.; Cox, P. A.

In: Neurotoxicity Research, 19.05.2017, p. 1-7.

Research output: Contribution to journalArticle

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