Circulating miRNAs as Biomarkers for Mitochondrial Neuro-Gastrointestinal Encephalomyopathy

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease for which there are currently no validated outcome measures for assessing therapeutic intervention efficacy. The aim of this study was to identify a plasma and/or serum microRNA (miRNA) biomarker panel for MNGIE. Sixty-five patients and 65 age and sex matched healthy controls were recruited and assigned to one of four study phases: (i) discovery for sample size determination; (ii) candidate screening; (iii) candidate validation; and (iv) verifying the performance of the validated miRNA panel in four patients treated with erythrocyte-encapsulated thymidine phosphorylase (EE-TP), an enzyme replacement under development for MNGIE. Quantitative PCR (qPCR) was used to profile miRNAs in serum and/or plasma samples collected for the discovery, validation and performance phases, and next generation sequencing (NGS) analysis was applied to serum samples assigned to the candidate screening phase. Forty-one differentially expressed candidate miRNAs were identified in the sera of patients (p < 0.05, log2 fold change > 1). The validation cohort revealed that of those, 27 miRNAs were upregulated in plasma and three miRNAs were upregulated in sera (p < 0.05). Through binary logistic regression analyses, five plasma miRNAs (miR-192-5p, miR-193a-5p, miR-194-5p, miR-215-5p and miR-34a-5p) and three serum miRNAs (miR-192-5p, miR-194-5p and miR-34a-5p) were shown to robustly distinguish MNGIE from healthy controls. Reduced longitudinal miRNA expression of miR-34a-5p was observed in all four patients treated with EE-TP and coincided with biochemical and clinical improvements. We recommend the inclusion of the plasma exploratory miRNA biomarker panel in future clinical trials of investigational therapies for MNGIE; it may have prognostic value for assessing clinical status.

Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice

“…The stimulation from several molecules during sepsis alters brain and neuron activities, including the production of several microRNAs (miRs; a small endogenous non-coding RNA), RNA, and proteins (such as cytokines). Among different brain-induced miRs during sepsis, miR370-3p is highly expressed in the brain and can be detected in serum, which has been proposed as a biomarker for SE status [18,19] and possibly is associated with cell energy [20][21][22]. Because (i) the energy status of different cell types might be important in sepsis [23], (ii) BAM15 attenuates sepsis in the LPS injection mouse model, partly through the manipulations in the energy status of hepatocytes and RAW264.7 cells (macrophages) [24], and (iii) miR370-3p is highly upregulated in brain cells during sepsis [18], we hypothesize that miR370-3p might be associated with brain cell energy and BAM15 might attenuate sepsis severity in multiple organs, including the brain, through the energy interference.…”

Biomarkers in Rare Diseases 2.0

“…The second article focusing on mitochondrial disease is an excellent example of an international collaborative effort between ten countries and 20 collaborators. In their four-phase study, Mencias and co-workers investigated the utility of microRNAs (miRNAs) as potential circulating biomarkers of the ultra-rare disease, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) [3]. Of the five plasma miRNAs and three serum miRNAs that could robustly distinguish MNGIE disease from healthy controls, the single best predictor was miR-34a-5p.…”