MicroRNA signature associated with treatment response in myasthenia gravis: a further step towards precision medicine.

MicroRNA signature associated with treatment response in myasthenia gravis: a further step towards precision medicine.

Publication date: Aug 08, 2019

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.

Cavalcante, P., Mizrachi, T., Barzago, C., Scandiffio, L., Bortone, F., Bonanno, S., Frangiamore, R., Mantegazza, R., Bernasconi, P., Brenner, T., Vaknin-Dembinsky, A., and Antozzi, C. MicroRNA signature associated with treatment response in myasthenia gravis: a further step towards precision medicine. 05166. 2019 Pharmacol Res.

Concepts Keywords
Autoimmune Disorder Chronic immunosuppression Inter
Biomarkers MG autoimmune disorder
Blood Myasthenia gravis
Chromosome Immunosuppression
Drug Metabolism Immunosuppressive therapies
Immunosuppression Branches of biology
Immunosuppressive RNA
Immunosuppressive Drugs Gene expression
Indicative Medicine
Italian MicroRNA
MG Biomarkers
MicroRNA Myasthenia gravis
MiRNA Drug metabolism
Modulation
MRNA
Myasthenia Gravis
Neuromuscular Transmission
Neurotrophin
Ontology
Precision Medicine
Real Time PCR
Receptor
ROC Curve
Sequencing
TRK

Semantics

Type Source Name
drug DRUGBANK Spinosad
gene UNIPROT NTRK1
drug DRUGBANK Saquinavir
gene UNIPROT MLXIP
gene UNIPROT MYLIP
gene UNIPROT MARCH8
gene UNIPROT PTPN5
disease DOID myasthenia gravis
disease MESH myasthenia gravis

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