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

Author:

Alarcan Hugo12ORCID,Bruno Clément3,Emond Patrick24,Raoul Cédric56,Vourc'h Patrick12,Corcia Philippe27,Camu William56,Veyrune Jean‐Luc8,Garlanda Cecilia910,Locati Massimo10,Juntas‐Morales Raúl11,Saker Safaa12,Suehs Carey13,Masseguin Christophe14,Kirby Janine15,Shaw Pamela15,Malaspina Andrea16,De Vos John17,Al‐Chalabi Ammar18,Leigh P. Nigel19,Tree Timothy20,Bensimon Gilbert13,Blasco Hélène12

Affiliation:

1. Service de Biochimie et Biologie Moléculaire CHRU Bretonneau Tours France

2. UMR 1253 iBrain Université de Tours, Inserm Tours France

3. Service de Pharmacologie Médicale CHRU Bretonneau Tours France

4. Laboratoire de Médecine nucléaire in vitro CHRU Bretonneau Tours France

5. INM University of Montpellier, INSERM Montpellier France

6. ALS Reference Center University of Montpellier, CHU Montpellier Montpellier France

7. Service de Neurologie CHRU Bretonneau Tours France

8. Institute of Human Genetics University of Montepllier Montpellier France

9. Department of Biomedical Sciences Humanitas University Milan Italy

10. IRCCS Humanitas Research Hospital Rozzano Italy

11. Neuromuscular Diseases Unit, European Reference Network on Rare Neuromuscular Diseases (ERN EURO‐NMD), Department of Neurology Vall d'Hebron University Hospital Barcelona Spain

12. Genethon, DNA and Cell bank Evry France

13. Laboratoire de Biostatistique, Epidémiologie clinique, Santé Publique, Innovation et Méthodologie (BESPIM) Université de Nîmes Nîmes France

14. Delegation for Clinical Research and Innovation Nîmes University Hospital Nîmes France

15. Sheffield Institute for Translational Neuroscience (SITraN) University of Sheffield Sheffield UK

16. UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology University College London, Queen Square London UK

17. Department of Cell and Tissue Engineering University Montpellier, CHU Montpellier Montpellier France

18. Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute King's College London London UK

19. Brighton and Sussex Medical School Brighton UK

20. Department of Computer Science University of Sheffield Sheffield UK

Abstract

AbstractAmyotrophic 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.

Publisher

Wiley

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