Evaluation of Diagnostic Performance of Circulating microRNAs as Biomarkers of Retinal Toxicity in the Rat.

Retinal toxicity is of great concern during drug development due to the irreversibility. Circulating microRNA (miRNA) is reported to be useful for detecting retinal toxicity in rats, although there has been no assessment of the diagnostic performance with statistical analysis. Therefore, we comparatively analyzed the diagnostic performance of circulating miRNAs enriched in the retina such as rno-miR-124-3p, -183-5p, -96-5p, -182, -9a-5p, -125b-5p, -204-5p and -211-5p. The toxicants used in this study resulted in three types of retinal injury in photoreceptor (PR) cells, neuroretinal (NR) cells and retinal pigment epithelium (RPE) cells in rats. The performance of these biomarkers of retinal toxicity were assessed by receiver operator characteristic (ROC) analysis, then cut-off values indicating the histopathological retinal lesions and performance indexes such as area under the ROC curve (ROC-AUC), sensitivity and specificity were calculated. The ROC-AUC for PR cell toxicity in relation to rno-miR-183-5p and -182 were 0.970 and 0.873, respectively, and for NR cell toxicity in relation to rno-miR-124-3p it was 0.896. Our results suggest that plasma rno-miR-124-3p and -183-5p/-182 would be suitable for detecting NR cell toxicity and PR cell toxicity, respectively. In conclusion, these plasma miRNAs may be an effective screening tool to detect drug-induced retinal toxicity in preclinical toxicology studies.