Blood-based untargeted metabolomics in rrms revealed the testable therapeutic target
Cerghet M, Poisson L, Suhail H, Singh J, Datta I, Mangalam A, Elias SB, Rattan R, and Giri S. Blood-based untargeted metabolomics in rrms revealed the testable therapeutic target. Multiple Sclerosis Journal 2019; 25(Suppl 1):22.
Multiple Sclerosis Journal
Background: Relapsing-remitting (RRMS), a most common form of MS, is characterized by acute attacks alternated by partial or complete recovery periods. Objectives: The major focus of our research is to identify the therapeutic target using metabolomics. Metabolomics is a fast emerging field which can provide a direct “functional readout of the physiological state” of an organism. Identification of bloodbased metabolic pathway(s) in relapsing-remitting form of MS (RRMS) could be targeted for therapy development. Methods: Using ultra-performance liquid chromatography linked to gas chromatography and tandem mass spectrometry (Metabolon, Durham, NC), we measured serum metabolites from 35 RRMS subjects without any drug treatment (mean age: 45 years and mean duration of disease 18.2 years; 64% female) and 14 healthy subjects with no disease (mean age: 40 years; 64% female). Results: Using untargeted ultra-performance liquid and gas mass spectrometry, we measured serum metabolites from 33 RRMS patients, and 14 healthy subjects (HS). A total of 621 known metabolites were detected, and 60 metabolites were significantly altered in the serum of RRMS compared to HS. Bioinformatics analysis revealed four metabolic pathways altered in RRMS including glycerophospholipid, citrate cycle, sphingolipids, and pyruvate metabolism. PBMCs isolated from RRMS patients exhibited higher glycolysis suggesting altered metabolic state of immune cells. As a proof of principle, we are abrogating glycolysis in EAE group using glycolytic inhibitor (once daily) and found a significant reduction (P<0.001) in the disease progression. Conclusion: Using untargeted metabolomic and Seahorse bioanalyzer approaches, we document that RRMS patients showed altered metabolic state “metabotype.” Targeting glycolysis, upstream of four metabolic pathways altered in RRMS, using pharmacological inhibitor ameliorated the disease progression in a preclinical model of MS.