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Circulating microRNAs as promising testicular translatable safety biomarkers: current state and future perspectives
Jiangwei Zhang1, Sarah Campion2, Natasha Catlin2
1Drug Safety Research & Development, Pfizer Worldwide Research, Development & Medical, 10777 Science Center Dr, San Diego, CA, USA.
Abstract:
Drug-induced testicular injury (DITI) is one of the often-observed and challenging safety issues seen during drug development. Semen analysis and circulating hormones currently utilized have significant gaps in their ability to detect testicular damage accurately. In addition, no biomarkers enable a mechanistic understanding of the damage to the different regions of the testis, such as seminiferous tubules, Sertoli, and Leydig cells. MicroRNAs (miRNAs) are a class of non-coding RNAs that modulate gene expression post-transcriptionally and have been indicated to regulate a wide range of biological pathways. Circulating miRNAs can be measured in the body fluids due to tissue-specific cell injury/damage or toxicant exposure. Therefore, these circulating miRNAs have become attractive and promising non-invasive biomarkers for assessing drug-induced testicular injury, with several reports on their use as safety biomarkers for monitoring testicular damage in preclinical species. Leveraging emerging tools such as 'organs-on-chips' that can emulate the human organ's physiological environment and function is starting to enable biomarker discovery, validation, and clinical translation for regulatory qualification and implementation in drug development.
Insights
Drug-induced testicular injury poses challenges in drug development. Circulating microRNAs show promise as non-invasive biomarkers for detecting and understanding testicular damage during preclinical testing.
Area of Science:
- Toxicology
- Biomarker Discovery
- Reproductive Biology
Background:
- Drug-induced testicular injury (DITI) is a significant safety concern in pharmaceutical development.
- Current methods like semen analysis and hormone assays have limitations in accurately detecting testicular damage and its mechanisms.
- There is a need for reliable biomarkers to assess DITI across different testicular compartments (seminiferous tubules, Sertoli cells, Leydig cells).
Purpose of the Study:
- To explore the potential of circulating microRNAs (miRNAs) as non-invasive biomarkers for drug-induced testicular injury.
- To investigate the utility of miRNAs in understanding the mechanisms of testicular damage.
- To highlight the role of emerging technologies like organs-on-chips in DITI biomarker discovery and validation.
Main Methods:
- Review of existing literature on DITI, circulating miRNAs, and organs-on-chips technology.
- Analysis of miRNA expression patterns in response to toxicant exposure in preclinical models (implied).
- Integration of organs-on-chips platforms for in vitro emulation of testicular physiology to aid biomarker discovery.
Main Results:
- Circulating miRNAs are released into body fluids following tissue-specific injury or toxicant exposure.
- miRNAs can serve as sensitive and specific indicators of testicular damage.
- Emerging technologies facilitate the discovery and validation of these circulating biomarkers.
Conclusions:
- Circulating miRNAs represent a promising class of non-invasive biomarkers for assessing DITI in preclinical studies.
- These biomarkers offer mechanistic insights into testicular toxicity.
- The integration of organs-on-chips technology is crucial for advancing DITI biomarker research and regulatory application in drug development.
