title: 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.
authors.affiliation: *Drug Safety Research and Development; qinghai.peng@pfizer.com.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Peng
authors.affiliation: *Drug Safety Research and Development;
authors.forename: Walter
authors.initials: W
authors.lastname: Collette
authors.affiliation: Global Science and Technology, Comparative Medicine, Pfizer Global Research and Development, San Diego, California 92121.
authors.forename: Anand
authors.initials: A
authors.lastname: Giddabasappa
authors.affiliation: Global Science and Technology, Comparative Medicine, Pfizer Global Research and Development, San Diego, California 92121.
authors.forename: John
authors.initials: J
authors.lastname: David
authors.affiliation: *Drug Safety Research and Development;
authors.forename: Michelle
authors.initials: M
authors.lastname: Twamley
authors.affiliation: *Drug Safety Research and Development;
authors.forename: Dalia
authors.initials: D
authors.lastname: Kalabat
authors.affiliation: *Drug Safety Research and Development;
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Aguirre
authors.affiliation: *Drug Safety Research and Development; qinghai.peng@pfizer.com.
authors.forename: Wenhu
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D004596:Electroretinography; D005260:Female; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000187:drug effects* / Q000503:physiopathology; D018675:Toxicity Tests
chemical_list: D015415:Biomarkers; D035683:MicroRNAs
keywords: LCM and CNV.; biomarker; electroretinogram; miRNAs; retinal toxicity