Phase I clinical trial of safety of L-serine for ALS patients

Levine, Todd; Miller, Robert G.; Bradley, Walter G.; Moore, Dan H.; Saperstein, David; Flynn, Lynne E.; Katz, Jonathan; Forshew, Dallas; Metcalf, James S.; Banack, Sandra Anne; Cox, Paul Alan

doi:10.1080/21678421.2016.1221971

Cited by 62 publications

(55 citation statements)

References 19 publications

(21 reference statements)

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“…It is therefore important to pay special attention to skin changes in future trials for HSAN1C. The overall tolerance of L-serine in our patient is in line with its reported safety in the previous trial for ALS where the highest dose was 30 g/day for up to 6 mo ( Levine et al 2017 ), HSAN1A where doses reached 400 mg/kg/day ( Garofalo et al 2011 ), and a toxicity study in rats using daily doses of up to 2900 mg/kg ( Tada et al 2010 ). The use of nortriptyline by our patient is important to note.…”

Section: Discussionsupporting

confidence: 84%

“…Therefore, L-serine is being tested as a treatment for HSAN1A (clinicaltrials.gov; NCT01733407) but so far the supplementation is untested in HSAN1C. L-serine supplementation is also used in congenital disorders of L-serine synthesis ( El-Hattab 2016 ) and has been tested as a potential neuroprotective agent in amyotrophic lateral sclerosis (ALS) ( Levine et al 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C

Auranen

Toppila

Suriyanarayanan

et al. 2017

Cold Spring Harb Mol Case Stud

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Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far untested in HSAN1C caused by variants in the serine palmitoyl transferase subunit 2 (SPTLC2) gene. The aim of this study was to establish whether oral L-serine lowers 1-deoxySL in a patient with HSAN1C, to perform a dose escalation to find the minimal effective dose, and to assess the safety profile and global metabolic effects of the treatment. Our patient underwent a 52-wk treatment in which the L-serine dose was titrated up to 400 mg/kg/day. She was followed up by repeated clinical examination, nerve conduction testing, and skin biopsies to document effects on small nerve fibers. Serum was assayed for 1-deoxySL and metabolomics analysis of 111 metabolites. We found a robust lowering of 1-deoxySL, which correlated in a near-linear fashion with increased serum L-serine levels. Metabolomics analysis showed a modest elevation in glycine and a marked reduction in the level of cytosine, whereas most of the other assayed metabolites did not change. There were no direct side effects from the treatment, but the patient developed a transitory toe ulceration during the course of the study. The Charcot–Marie–Tooth neuropathy score increased by 1 point. We conclude that oral supplementation of L-serine decreases 1-deoxySL in HSAN1C without major global effects on metabolism. L-serine is therefore a potential treatment for HSAN1C.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C

Auranen

Toppila

Suriyanarayanan

et al. 2017

Cold Spring Harb Mol Case Stud

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“…A 10% serine-enriched diet reduced neurotoxic deoxysphingolipid plasma levels both in transgenic mice expressing the p.C133W SPTLC1 mutation and in human patients diagnosed with hereditary sensory and autonomic neuropathy, type 1A (HSAN1) (28). Furthermore, a safety trial involving twenty ALS patients demonstrated that up to 30 grams of oral serine per day are well-tolerated over six months of treatment and that this polar amino acid is actively transported across the blood-brain barrier (29). We are hopeful that serine supplementation might have similar beneficial effects in SPTLC1-related ALS as that observed for HSAN1.…”

Section: Discussionmentioning

confidence: 99%

Mutations in the SPTLC1 gene are a cause of juvenile amyotrophic lateral sclerosis that may be amenable to serine supplementation

Johnson¹,

Chia²,

De³

et al. 2019

Preprint

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AbstractJuvenile amyotrophic lateral sclerosis (ALS) is a rare form of childhood motor disorder with a heterogeneous clinical presentation. The underlying causes of this condition are poorly understood, hindering the development of effective therapies. In a whole-exome sequencing trio-family study of three unrelated juvenile patients diagnosed with ALS and failure to thrive, we identified de-novo mutations in SPTLC1 (p.Ala20Ser in two patients and p.Ser331Tyr) not present in their healthy parents or siblings. SPTLC1 encodes a subunit of the serine palmitoyltransferase complex, a key enzyme in sphingolipid biosynthesis. Mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A, with a characteristic increase in plasma levels of neurotoxic deoxymethyl-sphinganine. We found an increase of this metabolite in one of our patients carrying the p.Ala20Ser mutation. Treatment of one of the patients with high dose, oral L-serine led to an increase in body weight, suggesting that serine supplementation may be beneficial among patients carrying mutations in this gene.

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“…Another link to a possible role of L‐serine in preserving neurons comes from studies of Alzheimer's disease and amyotrophic lateral sclerosis (ALS), in which clinical trials with L‐serine are ongoing. A phase 1 human trial for ALS showed that patients receiving the highest dose of 30 g/day had a reduced rate of functional loss compared to control patients .…”

mentioning

confidence: 99%

L‐serine: a neglected amino acid with a potential therapeutic role in diabetes

Holm

Buschard

2019

APMIS

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L‐serine is classified as a non‐essential amino acid; however, L‐serine is indispensable having a central role in a broad range of cellular processes. Growing evidence suggests a role for L‐serine in the development of diabetes mellitus and its related complications, with L‐serine being positively correlated to insulin secretion and sensitivity. L‐serine metabolism is altered in type 1, type 2, and gestational diabetes, and L‐serine supplementations improve glucose homeostasis and mitochondrial function, and reduce neuronal death. Additionally, L‐serine lowers the incidence of autoimmune diabetes in NOD mice. Dietary supplementations of L‐serine are generally regarded as safe (GRAS) by the FDA. Therefore, we believe that L‐serine should be considered as an emerging therapeutic option in diabetes, although work remains in order to fully understand the role of L‐serine in diabetes.

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Phase I clinical trial of safety of L-serine for ALS patients

Cited by 62 publications

References 19 publications

Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C

Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C

Mutations in the SPTLC1 gene are a cause of juvenile amyotrophic lateral sclerosis that may be amenable to serine supplementation

L‐serine: a neglected amino acid with a potential therapeutic role in diabetes

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