Circulating liver-specific microRNAs in cynomolgus monkeys.

Area of Science:

• Biomarkers
• Toxicology
• Molecular Biology

Background:

• Circulating microRNAs (miRNAs) are promising biomarkers for tissue injury.
• Limited data on organ-specific miRNAs in nonhuman primates hinders their use in toxicological studies.
• Cynomolgus monkey miRNAs are investigated for organ specificity and potential as safety biomarkers.

Purpose of the Study:

• Identify and characterize organ-specific miRNAs in cynomolgus monkeys.
• Quantify circulating levels of specific miRNAs (miR-122, miR-192).
• Evaluate the utility of circulating miRNAs as biomarkers in a drug-induced hepatotoxicity model.

Main Methods:

• Next-generation sequencing to identify organ-specific miRNAs.
• Quantitative reverse transcription polymerase chain reaction (RT-qPCR) for miRNA quantification.
• Acetaminophen-induced hepatotoxicity model in cynomolgus monkeys.

Main Results:

• miR-122 was liver-specific; miR-192 was found in liver, stomach, intestines, and kidney.
• Sequences of cynomolgus monkey miRNAs matched human counterparts.
• Circulating miR-122 and miR-192 levels increased significantly post-acetaminophen exposure, preceding ALT elevation.
• Greater interindividual variation observed for miR-122 compared to miR-192.

Conclusions:

• Circulating miR-122 and miR-192 are valuable liver-specific biomarkers in cynomolgus monkeys.
• These miRNAs can serve as sensitive indicators of drug-induced hepatotoxicity.
• Findings support the use of circulating miRNAs in nonclinical safety assessments.