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Precision-cut organ slices to investigate target organ injury
Alison E M Vickers1, Robyn L Fisher
1Allergan, Inc., RD2-2A, 2525 DuPont Drive, Irvine CA 92623, USA. vickers_alison@allergan.com
Abstract:
Drug-induced organ injury is a multifaceted process, involving numerous cell types and mediators, and remains a significant safety issue in pharmaceutical development and clinical therapy. Organ slices, an in vitro model representing the multicellular, structural and functional features of in vivo tissue, is a promising model for elucidating mechanisms of drug-induced organ injury and for characterising species susceptibilities. Time- and concentration-dependent drug-induced effects on organ slice gene expression, function and morphology are providing insight into the molecular and biochemical pathways leading to organ dysfunction, an altered morphology and the induction of repair pathways. Human organ slice studies are valuable for bridging the extrapolation of animal-derived data and for identifying mechanisms relevant for humans. The liver is the major organ used in organ slice studies; however, the utility of extrahepatic-derived slices, as well as cocultures for investigating multiple organ involvement in tissue injury is increasing. Organ slice investigations can further our understanding of the cell types and cell interactions involved in drug-induced injury and the consequences of drug-induced off-target effects for identifying compound liabilities that will impact safety.
Insights
Organ slices are a promising in vitro model to study drug-induced organ injury mechanisms and species differences. These multicellular tissue models provide insights into molecular pathways and aid in identifying safety liabilities for pharmaceuticals.
Area of Science:
- Toxicology
- Drug Development
- In Vitro Models
Background:
- Drug-induced organ injury is a complex safety concern in pharmaceutical development.
- Existing models struggle to fully replicate in vivo tissue complexity.
- Organ slices offer a multicellular, structurally and functionally representative in vitro system.
Purpose of the Study:
- To highlight the utility of organ slices for studying drug-induced organ injury.
- To elucidate mechanisms of drug toxicity and species-specific responses.
- To identify compound liabilities impacting drug safety.
Main Methods:
- Utilizing organ slices as an in vitro model to assess drug effects.
- Analyzing time- and concentration-dependent changes in gene expression, function, and morphology.
- Investigating human organ slices to bridge animal data extrapolation.
- Exploring extrahepatic organ slices and cocultures for multi-organ injury studies.
Main Results:
- Organ slice studies reveal molecular and biochemical pathways of organ dysfunction.
- Insights into altered morphology and the induction of repair pathways are gained.
- Human organ slice data aids in predicting human-relevant mechanisms.
- Increasing use of extrahepatic and coculture models for broader injury assessment.
Conclusions:
- Organ slices are valuable for understanding drug-induced organ injury mechanisms and species susceptibility.
- These models enhance the prediction of compound safety liabilities.
- Organ slice technology advances pharmaceutical safety assessment and clinical therapy insights.
