Evaluation of Diagnostic Performance of Circulating microRNAs as Biomarkers of Retinal Toxicity in the Rat
Daichi Ishii1, Yuki Nishikawa1, Miharu Soeda1
1Safety Research Department, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Abstract:
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.
Insights
This study identifies specific circulating microRNAs (miRNAs) as reliable biomarkers for detecting drug-induced retinal toxicity in rats. Plasma rno-miR-124-3p and rno-miR-183-5p/-182 show promise for early screening of retinal damage.
Area of Science:
- Biomarkers
- Toxicology
- Ophthalmology
Background:
- Drug-induced retinal toxicity is a significant concern in drug development due to its irreversible nature.
- Circulating microRNAs (miRNAs) show potential for non-invasive detection of retinal toxicity.
- Previous assessments lacked rigorous statistical analysis of diagnostic performance.
Purpose of the Study:
- To comparatively analyze the diagnostic performance of specific circulating miRNAs for detecting retinal toxicity.
- To evaluate miRNAs enriched in the retina, including rno-miR-124-3p, -183-5p, -96-5p, -182, -9a-5p, -125b-5p, -204-5p, and -211-5p.
- To determine the efficacy of these miRNAs as screening tools for drug-induced retinal toxicity in preclinical studies.
Main Methods:
- Induction of retinal injury in photoreceptor (PR), neuroretinal (NR), and retinal pigment epithelium (RPE) cells in rats using toxicants.
- Assessment of biomarker performance using receiver operator characteristic (ROC) analysis.
- Calculation of cut-off values, area under the ROC curve (ROC-AUC), sensitivity, and specificity.
Main Results:
- ROC-AUC for PR cell toxicity: 0.970 for rno-miR-183-5p and 0.873 for rno-miR-182.
- ROC-AUC for NR cell toxicity: 0.896 for rno-miR-124-3p.
- Plasma rno-miR-124-3p and rno-miR-183-5p/-182 demonstrated suitability for detecting NR and PR cell toxicity, respectively.
Conclusions:
- Plasma rno-miR-124-3p and rno-miR-183-5p/-182 are potential biomarkers for drug-induced retinal toxicity.
- These miRNAs can serve as effective screening tools in preclinical toxicology studies.
- This approach aids in early detection and management of irreversible retinal damage during drug development.
