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

Hugo Alarcan^{1

2}, Clément Bruno³, Patrick Emond^{2

4}, Cédric Raoul^{5

6}, Patrick Vourc'h^{1

2}, Philippe Corcia^{2

7}, William Camu^{5

6}, Jean-Luc Veyrune⁸, Cecilia Garlanda^{9

10}, Massimo Locati¹⁰, Raúl Juntas-Morales¹¹, Safaa Saker¹², Carey Suehs¹³, Christophe Masseguin¹⁴, Janine Kirby¹⁵, Pamela Shaw¹⁵, Andrea Malaspina¹⁶, John De Vos¹⁷, Ammar Al-Chalabi¹⁸, P Nigel Leigh¹⁹, Timothy Tree²⁰, Gilbert Bensimon^#¹³, Hélène Blasco^#^{1

2}

Affiliations

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.

^# Contributed equally.

PMID: 38771698
DOI: 10.1111/nyas.15147

Clinical Trial

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

Hugo Alarcan et al. Ann N Y Acad Sci. 2024 Jun.

. 2024 Jun;1536(1):82-91.

doi: 10.1111/nyas.15147. Epub 2024 May 21.

Authors

Affiliations

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.

^# Contributed equally.

PMID: 38771698
DOI: 10.1111/nyas.15147

Abstract

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.

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References

REFERENCES

1. Hardiman, O., Al‐Chalabi, A., Chio, A., Corr, E. M., Logroscino, G., Robberecht, W., Shaw, P. J., Simmons, Z., & Van Den Berg, L. H. (2017). Amyotrophic lateral sclerosis. Nature Reviews Disease Primers, 3, 17071. https://doi.org/10.1038/nrdp.2017.71
1. Mead, R. J., Shan, N., Reiser, H. J., Marshall, F., & Shaw, P. J. (2023). Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nature Reviews Drug Discovery, 22(3), 185–212. https://doi.org/10.1038/s41573‐022‐00612‐2
1. Soares, P., Silva, C., Chavarria, D., Silva, F. S. G., Oliveira, P. J., & Borges, F. (2023). Drug discovery and amyotrophic lateral sclerosis: Emerging challenges and therapeutic opportunities. Ageing Research Reviews, 83, 101790. https://doi.org/10.1016/j.arr.2022.101790
1. Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., Mccluskey, L. F., Miller, B. L., Masliah, E., Mackenzie, I. R., Feldman, H., Feiden, W., Kretzschmar, H. A., Trojanowski, J. Q., & Lee, V. M.‐Y. (2006). Ubiquitinated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science, 314(5796), 130–133. https://doi.org/10.1126/science.1134108
1. Pasquali, L., Lenzi, P., Biagioni, F., Siciliano, G., & Fornai, F. (2014). Cell to cell spreading of misfolded proteins as a therapeutic target in motor neuron disease. Current Medicinal Chemistry, 21(31), 3508–3534. https://doi.org/10.2174/0929867321666140601161534

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

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

Authors

Affiliations

Abstract

References

REFERENCES

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Full Text Sources