A Minimally-invasive Blood-derived Biomarker of Oligodendrocyte Cell-loss in Multiple Sclerosis

• Currently, there are no molecular biomarkers of multiple sclerosis (MS).
• A minimally invasive assay for measuring oligodendrocyte (ODC) cell loss in relapsing-remitting MS is described.
• DNA methylation of the myelin oligodendrocyte glycoprotein gene is used as a measure of ODC loss in the blood.Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system. Currently, there are no molecular biomarkers of MS, thereby limiting disease diagnosis, prognosis, and assessment of new clinical interventions. Myelin oligodendrocyte glycoprotein (MOG) is expressed solely by oligodendrocytes (ODCs) as an integral part of the myelin sheath. This report describes a minimally invasive biomarker assay for measuring ODC-derived DNA in the blood of MS patients. It describes the presence of unique DNA methylation patterns in the MOG gene in ODCs, which is used to design methylation-specific primers. Analysis of sera from patients with active relapsing-remitting MS shows an increase in levels of ODC-derived circulating free DNA when compared with inactive disease and healthy controls.

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). Minimally invasive biomarkers of MS are required for disease diagnosis and treatment. Differentially methylated circulating-free DNA (cfDNA) is a useful biomarker for disease diagnosis and prognosis, and may offer to be a viable approach for understanding MS. Here, methylation-specific primers and quantitative real-time PCR were used to study methylation patterns of the myelin oligodendrocyte glycoprotein (MOG) gene, which is expressed primarily in myelin-producing oligodendrocytes (ODCs). MOG-DNA was demethylated in O4+ ODCs in mice and in DNA from human oligodendrocyte precursor cells (OPCs) when compared with other cell types. In the cuprizone-fed mouse model of demyelination, ODC derived demethylated MOG cfDNA was increased in serum and was associated with tissue-wide demyelination, demonstrating the utility of demethylated MOG cfDNA as a biomarker of ODC death. Collected sera from patients with active (symptomatic) relapsing-remitting MS (RRMS) demonstrated a higher signature of demethylated MOG cfDNA when compared with patients with inactive disease and healthy controls. Taken together, these results offer a minimally invasive approach to measuring ODC death in the blood of MS patients that may be used to monitor disease progression.