Editor's Highlight: Plasma miR-183/96/182 Cluster and miR-124 are Promising Biomarkers of Rat Retinal Toxicity

Abstract

Retinal toxicity is one of the leading causes of attrition in drug development, and drug-induced retinal toxicity remains an issue in both drug discovery and postmarketed drugs. Derisking strategies to help with early identification of retinal injury utilizing a predictive retinal miRNA biomarker would greatly benefit decision-making in drug discovery programs, ultimately reducing attrition due to retinal toxicity. Our previous work demonstrated elevation of circulating retina-enriched miRNAs in a retinal toxicity model. To further validate our previous observation, 2 additional rat retinal injury models were utilized in this study: NaIO3-induced retinal injury and laser-induced choroidal neovascularization (CNV) injury model. Following induction of retina tissue injuries, circulating miR-183/96/182 cluster (miR-183 cluster), and miR-124 was investigated, as well as evaluations using an electroretinogram (ERG) and histopathology analysis. Data revealed that circulating miR-183/96/182 cluster was significantly increased (2- to 15-fold) compared with baseline/control in both laser-induced CNV and NaIO3-induced retinal injury models. Moreover, the severity of the retinal injury evaluated by ERG and histopathology correlated highly with elevation of these retina-enriched miRNAs in plasma. MiR-124 was also significantly increased in comparison with baseline/control by ∼25-fold postrepeat-doses of 30 mg/kg NaIO3 treatment. Increased level of these plasma miRNA biomarkers appeared to be dose- and time-dependent upon NaIO3 or laser treatment. The results suggest that the retina-enriched miRNAs (miR-183/96/182 cluster and miR-124) could serve as convenient and predictive biomarkers of retinal toxicity in drug development.