MicroRNA signature associated with treatment response in myasthenia gravis: A further step towards precision medicine. (October 2019)

• Record Type: Journal Article
• Authors: Cavalcante, Paola; Mizrachi, Tehila; Barzago, Claudia; Scandiffio, Letizia; Bortone, Federica; Bonanno, Silvia; Frangiamore, Rita; Mantegazza, Renato; Bernasconi, Pia; Brenner, Talma; Vaknin-Dembinsky, Adi; Antozzi, Carlo
• Is Part Of: Pharmacological research. Volume 148(2019)
• Publication Date: 2019-10
• Subjects: ABCC ATP-binding cassette ABC sub-family C -- AChR acetylcholine receptor -- AUC area under curve -- BCR B cell receptor -- CREB1 cAMP responsive element binding protein 1 -- GNB1 G protein subunit beta 1 -- GO gene ontology -- IL interleukin -- logFC log fold change -- MAP2K1 mitogen-activated protein kinase kinase 1 -- MG myasthenia gravis -- NF-κB nuclear factor kappa B -- NGS next-generation sequencing -- NR non-responder -- NR3C1 nuclear receptor subfamily 3 group C member 1 -- QMG quantitative myasthenia gravis -- R responder -- RAC1 Rac family small GTPase 1 -- ROC receiver operating characteristic -- SPP1 secreted phosphoprotein 1 -- TLR toll-like receptor -- TNF tumor necrosis factor -- TRK tropomyosin-related kinase; Myasthenia gravis -- MicroRNAs -- Immunosuppressive treatment -- Drug response -- Biomarkers -- Precision medicine; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104388
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission currently treated with chronic immunosuppression. Inter-subject variation in treatment response and side effects highlight the need for personalized therapies by identification of biomarkers predictive of drug efficacy in individual patients, still lacking in MG. MicroRNAs (miRNAs) play a key role in immune response and drug metabolism modulation. This study, part of an Italian-Israeli collaborative project, aimed to identify specific miRNAs as biomarkers associated with immunosuppressive treatment response in MG patients. Whole miRNome sequencing, followed by miRNA validation by real-time PCR, was performed in peripheral blood from Italian MG patients (n = 40) classified as responder and non-responder to immunosuppressive therapies. MiRNA sequencing identified 41 miRNAs differentially expressed in non-responder compared to responder Italian MG patients. Validation phase pointed out three miRNAs, miR-323b-3p, -409-3p, and -485-3p, clustered on chromosome 14q32.31, the levels of which were significantly decreased in non-responder versus responder patients, whereas miR-181d-5p and -340-3p showed an opposite trend. ROC curve analysis showed sensitivity and specificity performance results indicative of miR-323b-3p, -409-3p, and -485-3p predictive value for responsiveness to immunosuppressive drugs in MG. Validated miRNAs were further analyzed in blood from responder and non-responder MG patients of the Israeli population (n = 33), confirming a role for miR-323b-3p, -409-3p, -485-3p, -181d-5p and -340-3p as biomarkers of drug efficacy. Gene Ontology enrichment analysis, mRNA target prediction, and in silico modeling for function of the identified miRNAs disclosed functional involvement of the five miRNAs, and their putative target genes, in both immune (i.e. neurotrophin TRK and Fc-epsilon receptor signaling pathways) and drug metabolism processes. Our overall findings thus revealed a blood "miR-323b-3p, -409-3p, -485-3p, -181d-5p, and -340-3p" signature associated with drug responsiveness in MG patients. Its identification sets the basis for precision medicine approaches based on "pharmacomiRs" as biomarkers of drug responsiveness in MG, promising to improve therapeutic success in a cost/effective manner.