Contributions
Abstract: P409
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Background: Glatiramer acetate (GA) is one of the first line therapy for relapsing-remitting multiple sclerosis (RRMS) treatment, although its targets on B cells are unknown. Mode of Action by NeTwoRk Analysis (MANTRA) identifies the drug"s molecular targets by building a “network of drugs” in which two compounds are connected if they elicit similar transcriptional responses. The smaller the drug distance (DD), the more similar the two compounds are. Drugs are partitioned into groups of interconnected compounds (communities) significantly enriched for drugs with similar mode of action (MoA).
Objectives: To identify B cells GA targets in RRMS patients using an integrated experimental and computational approach.
Methods: We enrolled 7 women treatment-naïve patients with RRMS according to Mc Donald criteria. All the patients didn"t receive corticosteroid treatment in the 30 days before the enrolment. B cells were isolated at baseline (in vitro) and after 6 months treatment (in vivo). At baseline, B cells were treated or not with 100µg/mL GA for 6h. B cells gene expression profiles of both in vitro and in vivo treatments were analyzed with MANTRA for MoA identification and with Gene Set Enrichment Analysis (GSEA) for the functional characterization of the genes.
Results: At baseline, MANTRA identified 7 communities when treated B cells were compared with non-treated B cells. All the communities were significantly associated to GA response (DD range 0.68-0.79). The compound with the smallest DD to GA (DD 0.68) was Ambroxol, a mucolytic agent that acts by blocking Na2+ channels and by reducing nitric oxide levels. GSEA results showed a significant down regulation of genes involved in ion channel activity in treated cells vs non treated cells (p< 0.001). After 6 months treatment, MANTRA identified 8 communities when in vivo GA treated cells were compared to non-treated cells, and 18 communities when compared to in vitro GA treated cells. In both cases, the smallest DDs were between GA and communities n.89, 90, 13, 14 and 61. The most enriched MoAs were CDK2 inhibitors (i.e. H-7 Dihydrochloride), topoisomerase II inhibitor (i.e. mitoxantrone) and inhibitor of potassium channels (i.e. gliclazide).
Conclusions: GA targets B cells in RRMS. Our data suggest a role for GA in inhibiting B cells activation and/or maturation by blocking ion channels, known to be essential for cell proliferation. Further analysis are needed to confirm the data.
Disclosure:
Chiara Criscuolo: nothing to disclose
Alessandra Cianflone: nothing to disclose
Claudia La Rocca: nothing to disclose
Giuseppe Matarese: nothing to disclose
Diego Carella: nothing to disclose
Diego Di Bernardo: nothing to disclose
Roberta Lanzillo: nothing to disclose
Vincenzo Brescia Morra: nothing to disclose
Abstract: P409
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Background: Glatiramer acetate (GA) is one of the first line therapy for relapsing-remitting multiple sclerosis (RRMS) treatment, although its targets on B cells are unknown. Mode of Action by NeTwoRk Analysis (MANTRA) identifies the drug"s molecular targets by building a “network of drugs” in which two compounds are connected if they elicit similar transcriptional responses. The smaller the drug distance (DD), the more similar the two compounds are. Drugs are partitioned into groups of interconnected compounds (communities) significantly enriched for drugs with similar mode of action (MoA).
Objectives: To identify B cells GA targets in RRMS patients using an integrated experimental and computational approach.
Methods: We enrolled 7 women treatment-naïve patients with RRMS according to Mc Donald criteria. All the patients didn"t receive corticosteroid treatment in the 30 days before the enrolment. B cells were isolated at baseline (in vitro) and after 6 months treatment (in vivo). At baseline, B cells were treated or not with 100µg/mL GA for 6h. B cells gene expression profiles of both in vitro and in vivo treatments were analyzed with MANTRA for MoA identification and with Gene Set Enrichment Analysis (GSEA) for the functional characterization of the genes.
Results: At baseline, MANTRA identified 7 communities when treated B cells were compared with non-treated B cells. All the communities were significantly associated to GA response (DD range 0.68-0.79). The compound with the smallest DD to GA (DD 0.68) was Ambroxol, a mucolytic agent that acts by blocking Na2+ channels and by reducing nitric oxide levels. GSEA results showed a significant down regulation of genes involved in ion channel activity in treated cells vs non treated cells (p< 0.001). After 6 months treatment, MANTRA identified 8 communities when in vivo GA treated cells were compared to non-treated cells, and 18 communities when compared to in vitro GA treated cells. In both cases, the smallest DDs were between GA and communities n.89, 90, 13, 14 and 61. The most enriched MoAs were CDK2 inhibitors (i.e. H-7 Dihydrochloride), topoisomerase II inhibitor (i.e. mitoxantrone) and inhibitor of potassium channels (i.e. gliclazide).
Conclusions: GA targets B cells in RRMS. Our data suggest a role for GA in inhibiting B cells activation and/or maturation by blocking ion channels, known to be essential for cell proliferation. Further analysis are needed to confirm the data.
Disclosure:
Chiara Criscuolo: nothing to disclose
Alessandra Cianflone: nothing to disclose
Claudia La Rocca: nothing to disclose
Giuseppe Matarese: nothing to disclose
Diego Carella: nothing to disclose
Diego Di Bernardo: nothing to disclose
Roberta Lanzillo: nothing to disclose
Vincenzo Brescia Morra: nothing to disclose