Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis

Ann N Y Acad Sci. 2024 Jun;1536(1):82-91. doi: 10.1111/nyas.15147. Epub 2024 May 21.


Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.

Keywords: amyotrophic lateral sclerosis; interleukin‐2; kynurenine pathway; metabolomics; pharmacometabolomics.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis* / drug therapy
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Female
  • Humans
  • Interleukin-2* / administration & dosage
  • Interleukin-2* / metabolism
  • Kynurenine / metabolism
  • Male
  • Metabolome / drug effects
  • Metabolomics* / methods
  • Middle Aged
  • T-Lymphocytes, Regulatory* / drug effects
  • T-Lymphocytes, Regulatory* / immunology
  • T-Lymphocytes, Regulatory* / metabolism


  • Interleukin-2
  • Kynurenine