Contributions
Abstract: P637
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: The mechanism of action of dimethyl fumarate (DMF) has not been fully elucidated. Modulation of the Nrf2 pathway was initially proposed as the mechanism of action of DMF, but more recently, DMF has been noted to bind the hydroxycarboxylic acid-2 (HCA2) receptor that also binds niacin and beta-hydroxybutyrate.
Goals: To utilize untargeted metabolomics to identify metabolic pathways affected by DMF in RRMS patients.
Methods: RRMS patients initiating DMF and healthy controls (age-, sex- and race-matched) were enrolled. Demographic information and blood samples (including peripheral blood mononuclear cells) were obtained at baseline and 6-months post-initiation (or at equivalent time for controls). Plasma from each time point was subjected to untargeted metabolomics analysis at Metabolon Inc.(Durham, NC). The metabolite concentrations obtained were then pre-processed (imputation of missing values, log transformation and scaling of variables). Data were then analyzed using a weighted correlation network analysis (WGCNA) approach to identify modules of highly correlated metabolites. We then used a generalized estimating equations (GEE) model to identify modules that were altered with DMF treatment in RRMS patients.
Results: 18 RRMS patients and 18 healthy controls were recruited. Metabolomics analyses identified 616 metabolites in the plasma of the participants. WGCNA identified 17 modules of highly-related metabolites. In subsequent GEE models, we identified three modules that were differentially altered in the RRMS group following DMF treatment. These modules consisted of phospholipids (phosphatidyl glycerols, phosphatidyl inositols and phosphatidyl cholines), which increased with DMF treatment (p=0.028), plasmalogens (anti-oxidant lipid species) and ascorbic acid metabolites (threonate, oxalate), which also increased (p=0.004), and fatty acids (saturated and poly-unsaturated fatty acids of variable chain lengths), which were reduced with DMF treatment (p=0.005). As expected, no change was observed in controls for these modules.
Conclusions: DMF treatment produced alterations in lipid metabolism, including increases in multiple phospholipids and plasmalogens and reductions in multiple fatty acids. Alterations in lipid metabolism, perhaps through the HCA2 receptor, could play a role in the immunological effects of DMF. Experiments to correlate the described changes in the metabolome, to changes in the immunophenotype with DMF treatment are ongoing.
Disclosure:
Dr. Bhargava is supported by an Insitutional Clinician Training Award from the NMSS.
Dr. Firtzgerald: nothing to disclose.
Dr. Kornberg is supported by a Clinician Scientist Training Award from the NMSS.
Matthew Smith: nothing to disclose.
Dr. Mowry is the PI of an investigator-intiated trial from Biogen, site PI of trials from Biogen and Sun Pharma and received free medication from Teva Neuroscience for a trial.
Dr. Calabresi has received grants to Johns Hopkins from Biogen, Novartis, and MedImmune, and has received honoraria for consulting from Vertex.His lab is supported by R01 NS082347 - Imaging neurodegeneration in multiple sclerosis
Supported by: An investigator initiated trial grant from Biogen.
Abstract: P637
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: The mechanism of action of dimethyl fumarate (DMF) has not been fully elucidated. Modulation of the Nrf2 pathway was initially proposed as the mechanism of action of DMF, but more recently, DMF has been noted to bind the hydroxycarboxylic acid-2 (HCA2) receptor that also binds niacin and beta-hydroxybutyrate.
Goals: To utilize untargeted metabolomics to identify metabolic pathways affected by DMF in RRMS patients.
Methods: RRMS patients initiating DMF and healthy controls (age-, sex- and race-matched) were enrolled. Demographic information and blood samples (including peripheral blood mononuclear cells) were obtained at baseline and 6-months post-initiation (or at equivalent time for controls). Plasma from each time point was subjected to untargeted metabolomics analysis at Metabolon Inc.(Durham, NC). The metabolite concentrations obtained were then pre-processed (imputation of missing values, log transformation and scaling of variables). Data were then analyzed using a weighted correlation network analysis (WGCNA) approach to identify modules of highly correlated metabolites. We then used a generalized estimating equations (GEE) model to identify modules that were altered with DMF treatment in RRMS patients.
Results: 18 RRMS patients and 18 healthy controls were recruited. Metabolomics analyses identified 616 metabolites in the plasma of the participants. WGCNA identified 17 modules of highly-related metabolites. In subsequent GEE models, we identified three modules that were differentially altered in the RRMS group following DMF treatment. These modules consisted of phospholipids (phosphatidyl glycerols, phosphatidyl inositols and phosphatidyl cholines), which increased with DMF treatment (p=0.028), plasmalogens (anti-oxidant lipid species) and ascorbic acid metabolites (threonate, oxalate), which also increased (p=0.004), and fatty acids (saturated and poly-unsaturated fatty acids of variable chain lengths), which were reduced with DMF treatment (p=0.005). As expected, no change was observed in controls for these modules.
Conclusions: DMF treatment produced alterations in lipid metabolism, including increases in multiple phospholipids and plasmalogens and reductions in multiple fatty acids. Alterations in lipid metabolism, perhaps through the HCA2 receptor, could play a role in the immunological effects of DMF. Experiments to correlate the described changes in the metabolome, to changes in the immunophenotype with DMF treatment are ongoing.
Disclosure:
Dr. Bhargava is supported by an Insitutional Clinician Training Award from the NMSS.
Dr. Firtzgerald: nothing to disclose.
Dr. Kornberg is supported by a Clinician Scientist Training Award from the NMSS.
Matthew Smith: nothing to disclose.
Dr. Mowry is the PI of an investigator-intiated trial from Biogen, site PI of trials from Biogen and Sun Pharma and received free medication from Teva Neuroscience for a trial.
Dr. Calabresi has received grants to Johns Hopkins from Biogen, Novartis, and MedImmune, and has received honoraria for consulting from Vertex.His lab is supported by R01 NS082347 - Imaging neurodegeneration in multiple sclerosis
Supported by: An investigator initiated trial grant from Biogen.