An RNA-seq study in Friedreich ataxia patients identified miR148a-3p as a putative prognostic biomarker of the disease.

Friedreich's Ataxia (FRDA) is a life-threatening hereditary ataxia with an incidence of 1:50,000 individuals in the Caucasian population and only one therapeutic drug approved solely in the United States. FRDA is a multi-systemic neurodegenerative disease; cardiac abnormalities are one of the major complications and the predominant cause of premature death. The onset of FRDA typically occurs between the ages of 5 and 15. Given the complexity and heterogeneity of the clinical features and the variability of their onset, the identification of biomarkers able to evaluate disease progression and to monitor the efficacy of treatments is essential to facilitate decision making in clinical practice. We performed an RNA-seq study evaluating the expression level of circulating small non-coding RNAs (sncRNA) on PBMCs of FRDA patients and of healthy donors (CTRL). A hierarchical clustering algorithm (HCA) detected a sncRNAs signature able to distin-guish CTRL from the majority of FRDA patients. Among the differentially expressed sncRNA, microRNAs are the most relevant group. Hsa-miR-148a-3p resulted significantly upregulated in FRDA plasma samples (p<0.05). Noteworthy, hsa-miR-148a-3p increase was significant also when LOFA (late onset FRDA patients) group was compared with control group (p<0.05). Analysis of ROC curve combining the expression values of hsa-miR-148a-3p and hsa-miR-223-3p, previously identified by our group and confirmed in this study, revealed an AUC of 0.86 with 95% confidence interval 0.77 to 0.95 (p-value <0.001). An in silico prediction analysis of target genes of both miRNA, indicated IL6ST gene, an interesting marker of neuroinflammation in FRDA, as a common target gene. Overall design: The identification of a miRNA profile occurring during the natural history of FRDA disease could be of relevance as miRNA levels change with disease progression and/or pharmacological interventions, and the identification of new miRNAs could contribute to the design of novel therapeutic strategies and improve clinical decisions. The aim of this study was to find a miRNA signature associated with the progression of the disease. Thus, we performed an RNA-seq study by NGS on peripheral blood mononuclear cells (PBMCs) of FRDA patients (grouped on the basis of the onset of clinical signs and severity; n=12) and one group of matched age and sex healthy donors (CTRL; n=4). Our study evaluated the expression level of circulating small non-coding RNAs (sncRNA), i.e not only miRNAs, but also snoRNAs, snRNAs and piRNAs. The 12 FRDA patients were chosen among those with an early onset of neurological symptoms (<14 years) and a worse course of the disease (named early-onset group, EOG, n= 4); those with an intermediate onset of neurological symptoms (14-25 years) and a slight disease course (intermediate-onset group, IOG, n= 4) and those with a late onset of neurological symptoms (>25 years) and a slow disease course (late-onset group, LOG, n= 4) .