Predictomics is a research project within the EU 6th Framework Program involving fourteen partners from nine European countries. Coordinated by José V. Castell (Foundation for Research, University Hospital La Fe, Valencia, Spain), this project aims at developing a novel platform for anticipating liver and kidney chronic toxicity elicited by drugs and xenobiotics. The outcomes of this research is expected to contribute to animal experimentation replacement in the field of chronic toxicity assessment.
Why this research?
Over 30% of drugs in development during the past decade failed because of mid-term toxicities in animals, or as result of unexpected adverse events in early clinical studies that could not be previously detected in pre-clinical studies .
The development of new drugs and the prediction of toxicity of compounds would be more efficient if good quality and human-relevant toxicological data could be available at earlier development stages.
While acute toxicity can be reasonably detected during the early pre-clinical studies, long-term toxicity is more difficult to predict, relying almost exclusively on animal experiments that frequently are not predictive enough for the human beings.(Up)
The needs...
Animal experimentation of this kind is expensive, time consuming, raises ethical issues and does not necessarily imply toxicological relevance to man.
Despite the efforts undertaken during past years to develop predictive in vitro tests for specific organ toxicity (i.e. isolated/perfused organs, tissue slices, primary cultures, cell lines organotypic cultures etc.) their reliability to anticipate chronic toxicity is very limited.
(Up)
Why i n vitro Research?
There is a clear need of well-standardized and robust in vitro models suitable for the screening of toxic and sub-chronic toxicity induced by xenobiotics.
The project Predictomis aims to develop an in vitro strategy that, by combining emerging technologies and advanced culture models, could be predictive of kidney and liver chronic toxicity elicited by drugs.(Up)
Specific Objectives of the project
Better understanding of the mechanisms of chronic toxicity to identify relevant early changes induced by chronic toxins.
Development of advanced and innovative cell culture models for liver and kidney cells, including targeted-directed cell transformation and stem cell technology.
To optimise and technologically improve genomic, proteomic and cytomic tools to increase their sensitivity and accuracy for toxicity studies.
Identification of primary (mechanistically linked) and secondary biomarkers of chronic toxicity based on combined genomic proteomic and cytomic analysis of cells exposed to model hepatotoxins and nephrotoxins.
Establishment of a hierarchical decision tree, based on the identified primary and secondary biomarkers, as well mathematical models to early anticipate the potential toxicity risk of drugs under development.
Prevalidation of the screening platform.(Up)
What makes this project singular?
The strength of this project will result from the combination of a comprehensive analysis of cell effects induced by toxicants by means of Cytomics/ Genomics/ Proteomics = Predictomics and a deeper mechanistic knowledge of drug-induced chronic toxicity.
Outstanding among these will be the identification of endpoints/pathways affected by the treatment with toxic compounds and the identification of sets of primary and secondary biomarkers classified according to their relevance to the mechanism of chronic toxicity.
The project aims to integrate emerging technologies and new culture models to develop a platform for chronic toxicity testing sufficiently robust and predictive as to undergo validation.
