Predicting human developmental toxicity of pharmaceuticals using human stem-like cells and metabolomics
First Claim
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1. A method of screening the teratogenicity of a test compound, the method comprising the steps of:
- (a) culturing human stem cell-like cells (hSLCs);
(i) in the presence of the test compound; and
(ii) in the absence of the test compound;
(b) determining the fold change in arginine associated with hSLCs cultured in the presence of the test compound in comparison with hSLCs cultured in the absence of the test compound;
(c) determining the fold change in asymmetric dimethyl arginine (ADMA) associated with hSLCs cultured in the presence of the test compound in comparison with hSLCs cultured in the absence of the test compound;
(d) determining the ratio of the fold change in arginine to the fold change in ADMA, wherein;
(i) a ratio of less than 0.9 or greater than 1.1 is indicative of the teratogenicity of the test compound; and
(ii) a ratio of greater than 0.9 and less than 1.1 is indicative of the non-teratogenicity of the test compound.
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Abstract
The invention provides biomarker profiles of metabolites and methods for screening chemical compounds including pharmaceutical agents, lead and candidate drug compounds and other chemicals using human stem-like cells (hSLCs) or lineage-specific cells produced therefrom. The inventive methods are useful for testing toxicity, particularly developmental toxicity and detecting teratogenic effects of such chemical compounds. Specifically, a more predictive developmental toxicity model, based on an in vitro method that utilizes both hSLCs and metabolomics to discover biomarkers of developmental toxicity is disclosed.
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Citations
11 Claims
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1. A method of screening the teratogenicity of a test compound, the method comprising the steps of:
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(a) culturing human stem cell-like cells (hSLCs); (i) in the presence of the test compound; and (ii) in the absence of the test compound; (b) determining the fold change in arginine associated with hSLCs cultured in the presence of the test compound in comparison with hSLCs cultured in the absence of the test compound; (c) determining the fold change in asymmetric dimethyl arginine (ADMA) associated with hSLCs cultured in the presence of the test compound in comparison with hSLCs cultured in the absence of the test compound; (d) determining the ratio of the fold change in arginine to the fold change in ADMA, wherein; (i) a ratio of less than 0.9 or greater than 1.1 is indicative of the teratogenicity of the test compound; and (ii) a ratio of greater than 0.9 and less than 1.1 is indicative of the non-teratogenicity of the test compound. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
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Specification