title: Circulating microRNAs as biomarkers of retinal toxicity.
abstract: Despite of the attrition due to retinal toxicity during drug development there are no early reliable predictive biomarkers of retinal toxicity and this is increasingly becoming a concern. Thus far, in pharmacology and toxicology the technologies for assessing retinal side effects are limited to inconvenient visual behavioral tests, invasive electroretinograms or terminal histopathology. To address the lack of convenient early predictive retinal toxicity biomarkers, we explored a set of potential novel retinal enriched miRNAs in rats ex vivo and in vivo with known retinal toxicant pan-CDK inhibitors to assess circulating plasma miRNAs in rats and non-retinal toxicants as controls. Rats were administered a single intravitreal (IVT) injection and blood samples were collected pre-dose, various time points post-dose and then analyzed for five retinal enriched miRNAs (miR-96, miR-124a, miR181a, miR-182 and miR-183) by qRT-PCR. Ophthalmic exam, electroretinogram and histopathology were performed as confirmatory tests. All five miRNAs tested in retinal explants culture were highly expressed after pan-CDK inhibitor treatment. In vivo the pan-CDK inhibitors caused elevations of miR-96, miR-124a and miR-183 in blood. These results highly correlated with ocular exam, electroretinograms and microscopic findings. Comparatively, there were no changes in miRNA levels, electroretinograms, or histopathology in the negative control treatment groups. Although these miRNAs need additional confirmatory evaluation whether they truly predict retinal toxicity prior to clinical observations and histopathology, these results provide promise for further testing using additional retinal toxicants.
authors.affiliation: Pfizer Global Research and Development, Drug Safety Research and Development, San Diego, CA, 92121, USA.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Peng
authors.forename: Wenhu
authors.initials: W
authors.lastname: Huang
authors.forename: Annette
authors.initials: A
authors.lastname: John-Baptiste
mesh_terms: D000818:Animals; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004596:Electroretinography; D005819:Genetic Markers; D058449:Intravitreal Injections; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D009924:Organ Culture Techniques; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D017208:Rats, Wistar; D012160:Retina / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D005819:Genetic Markers; C548144:MIRN124 microRNA, rat; C584645:MIRN183 microRNA, rat; C000591374:MIRN96 microRNA, rat; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases
keywords: drug-induced retinal toxicity; ocular toxicity; retinal enriched miRNA; retinal toxicity; retinopathy