Method of toxicological evaluation, method of toxicological screening and associated system
Inventors
Dumas, Marc-Emmanuel • LeClerc, Eric • Shintu, Laetitia • Baudoin, Regis • Legallais, Cécile • Toulhoat, Pierre • Brochot, Céline
Assignees
Institut National De L'environment Industriel Et Des Risques • Centre National de la Recherche Scientifique • Institut National de l'Environnement Industriel et des Risques • École Normale Supérieure de Lyon • University of Technology of Compiègne • Universite Technologie de Compiegne UTC
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Publication Number
US-9448226-B2
Publication Date
2016-09-20
Expiration Date
Abstract
The present invention relates to a method of toxicological evaluation of a candidate substance on at least one tissue or organ, characterized in that it comprises the steps of: (a) obtaining a bioartificial tissue or organ by simulation or modelling of the metabolic activity of said tissue or organ by at least one bioreactor; (b) exposure of said bioartificial tissue or organ to said substance; (c) observation of the metabolic response of the bioartificial tissue or organ and acquisition without a priori of an associated multidimensional data set; (d) identification by means of a method of multivariate statistical analysis of the components of the multidimensional data set which are quantitatively correlated with predetermined variables; (e) generation of a predictive model on the basis of the components of the data set that are actually retained; (f) testing of the predictive nature of said model by at least one statistical method of estimating reliability; (g) identification of the metabolic response of the bioartificial tissue or organ in the form of biomarkers associated with the components of the data set that are adopted for the model. The present invention also relates to a method of toxicological screening and to a system for this purpose.
Core Innovation
The invention relates to a method of toxicological evaluation and a method of toxicological screening of a candidate substance on at least one tissue or organ using a bioartificial tissue or organ obtained by simulation or modeling of the metabolic activity of said tissue or organ by at least one bioreactor. The bioartificial tissue or organ is exposed to the candidate substance by introducing the substance inside the at least one bioreactor during said at least one bioreactor functioning. A metabolic response is observed and an associated multidimensional data set is acquired without an a priori method.
The multidimensional data set is analyzed by a method of multivariate statistical analysis to identify components that are quantitatively correlated with predetermined variables. Based on the components of the data set actually selected, a predictive model is generated as a function between the predetermined variables and the selected components. The predictive nature of the predictive model is tested by at least one statistical method of estimating reliability.
The metabolic response is identified in the form of biomarkers associated with the components selected for the model. For toxicological screening, a specific toxicity signature is obtained from the list of biomarkers, and the biomarkers and/or the specific toxicity signature are compared with a bank of markers and/or toxicity signatures in order to identify the substance.
Claims Coverage
Two independent claims are identified. Both cover a bioreactor-based workflow that combines simulation/modeling-derived bioartificial tissues or organs, non-a priori acquisition of multidimensional metabolic response data, multivariate statistical selection of correlated components, predictive model generation with reliability testing, and translation into biomarker-based outputs; one claim further derives and compares a specific toxicity signature against a reference bank to identify the substance.
Simulation-modeled bioartificial tissue or organ in a bioreactor exposure
Obtaining a bioartificial tissue or organ by simulation or modeling of the metabolic activity of said tissue or organ by at least one bioreactor, and exposing said bioartificial tissue or organ to said substance by introducing said substance inside the at least one bioreactor during said at least one bioreactor functioning.
Non-a priori multidimensional metabolic response acquisition and multivariate correlated-component selection
Observing the metabolic response of the bioartificial tissue or organ and acquiring, without an a priori method, an associated multidimensional data set, and identifying by means of a method of multivariate statistical analysis the components of the multidimensional data set which are quantitatively correlated with predetermined variables.
Reliability-tested predictive model and biomarker identification
Generating a predictive model, consisting of a function between the predetermined variables and the components of the data set actually selected, on the basis of the components of the data set actually selected, testing of the predictive nature of said model by at least one statistical method of estimating reliability, and identifying the metabolic response of the bioartificial tissue or organ in the form of biomarkers associated with the components of the data set selected for the model.
Toxicity signature derivation and comparison to identify the substance
Obtaining a specific toxicity signature of said substance from the list of biomarkers obtained in step (g), and comparing the biomarkers and/or the specific toxicity signature with a bank of markers and/or toxicity signatures, so as to identify said substance.
Independent claim coverage centers on a bioreactor-exposed simulation/modeling-based bioartificial tissue or organ; acquisition of multidimensional metabolic response data without an a priori method; multivariate statistical identification of components correlated with predetermined variables; generation and reliability testing of a predictive model; translation to biomarkers, and, in the screening claim, derivation of a specific toxicity signature compared to a bank to identify the substance.
Stated Advantages
Enables toxicological evaluation and toxicological screening of a candidate substance using bioartificial tissue or organ in a bioreactor with multidimensional metabolic profiling and multivariate predictive modeling.
Produces biomarkers and a specific toxicity signature that can be compared with a bank of markers and/or toxicity signatures to identify the substance.
Documented Applications
Toxicological evaluation of a candidate substance on at least one tissue or organ using a bioartificial tissue or organ obtained by simulation or modeling and maintained in a bioreactor, followed by multidimensional metabolic response profiling and predictive modeling.
Toxicological screening of a candidate substance by deriving a specific toxicity signature from biomarkers and comparing the biomarkers and/or the signature with a bank of markers and/or toxicity signatures to identify the substance.
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