Predicting human developmental toxicity of pharmaceuticals using human stem-like cells and metabolomic ratios
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1. A method of screening the teratogenicity of a test compound, the method comprising:
- providing a test compound;
culturing undifferentiated human stem cell-like cells (hSLCs) in the presence of the test compound and in the absence of the test compound, wherein hSLCs are selected from the group consisting of human embryonic stem cells (hESCs), human induced pluripotent (iPS) cells, human embryoid bodies, and hSLC-derived lineage-specific cells;
determining the fold change in ornithine, or fragment, adduct, deduct or loss thereof, in the culture media of undifferentiated hSLCs cultured in the presence of the test compound in comparison with hSLCs cultured in the absence of the test compound;
determining the fold change in cystine, or fragment, adduct, deduct or loss thereof, in the culture media of undifferentiated hSLCs cultured in the presence of the test compound in comparison with hSLCs cultured in the absence of the test compound; and
determining the ratio of the fold change in ornithine, or fragment, adduct, deduct or loss thereof, to the fold change in cystine, or fragment, adduct, deduct or loss thereof, wherein a ratio of less than or equal to 0.88 is indicative of the teratogenicity of the compound, and a ratio of greater than 0.88 is indicative of the non-teratogenicity of the compound.
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Abstract
This present invention provides rapid, reproducible, biomarker-based screening methods for the developmental toxicity testing of compounds. The methods are designed to identify the exposure level at which a test compound perturbs metabolism in a manner predictive of developmental toxicity. In particular, the perturbation of two metabolites, ornithine and cystine, is measured, wherein a ratio of the fold change in ornithine to the fold change in cystine of less than or equal to about 0.88 is indicative of the teratogenicity of a test compound.
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15 Claims
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1. A method of screening the teratogenicity of a test compound, the method comprising:
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providing a test compound; culturing undifferentiated human stem cell-like cells (hSLCs) in the presence of the test compound and in the absence of the test compound, wherein hSLCs are selected from the group consisting of human embryonic stem cells (hESCs), human induced pluripotent (iPS) cells, human embryoid bodies, and hSLC-derived lineage-specific cells; determining the fold change in ornithine, or fragment, adduct, deduct or loss thereof, in the culture media of undifferentiated hSLCs cultured in the presence of the test compound in comparison with hSLCs cultured in the absence of the test compound; determining the fold change in cystine, or fragment, adduct, deduct or loss thereof, in the culture media of undifferentiated hSLCs cultured in the presence of the test compound in comparison with hSLCs cultured in the absence of the test compound; and determining the ratio of the fold change in ornithine, or fragment, adduct, deduct or loss thereof, to the fold change in cystine, or fragment, adduct, deduct or loss thereof, wherein a ratio of less than or equal to 0.88 is indicative of the teratogenicity of the compound, and a ratio of greater than 0.88 is indicative of the non-teratogenicity of the compound. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
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Specification