This project aims to develop the use of urinary exosomes as a non-invasive approach to assessing renal toxicity.
Renal toxicity is estimated to account for around 2% of drug attrition in preclinical development and 19% in phase III clinical trials. Improving the identification of kidney toxicity and to ensuring better translation of biomarkers has the potential to reduce and refine the use of animals.
Damage to the kidneys as a result of drug toxicity is assessed as part of preclinical studies in animals. They tend not to be standalone studies unless a specific toxicity has been identified which requires further investigation. Assessment typically focuses on circulating biomarkers of kidney damage such as serum creatinine levels and post-mortem tissue analysis, however, these provide little information on the cellular site of injury or the underlying pathophysiology.
The use of urinary exosomes provides an opportunity to non-invasively investigate renal toxicity. This has a number of 3Rs advantages; early signs of renal toxicity should allow decisions to be made to terminate studies before animals suffer, and longitudinal studies in the same animal should be possible allowing animals to be used as their own control. Importantly, improved biomarkers which translate to the clinic should allow drugs to be dropped earlier in the pipeline before the extensive animal testing required to support late stage clinical trials.
Research details and methods
Exosomes are nanoparticle-sized vesicles which transport a range of molecules including microRNAs. They are derived from derived from a range of cells and released into blood and urine. This research aims to investigate whether rat urinary exosomes can be used as a non-invasive marker of renal toxicity.
Urinary exosomes have been shown to capsulate microRNA originating from the glomerulus and nephron. Recent evidence suggests that microRNAs are mediators of drug toxicity and therefore may provide potential biomarkers of cell injury. The research will explore the utility and reproducibility of urinary exosomes for analysis of kidney toxicity. It will employ nanoparticle tracking analysis technology and antibody labelling to identify exosome concentration and cellular origin.
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- 2017 PhD Studentship Review: Case Study
Principal investigatorDr James Dear
InstitutionUniversity of Edinburgh
Co-InvestigatorDr Matthew Bailey
Professor David John Webb