Methods and platforms for drug discovery using induced pluripotent stem cells
First Claim
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1. A method for identifying an agent that corrects a phenotype associated with a health condition or a predisposition for the health condition, comprising:
- (i) contacting a first population of isolated cells differentiated from a human induced pluripotent stem cell line, wherein said cells exhibit a phenotype associated with the health condition or predisposition for the health condition, with a candidate agent;
(ii) contacting a second population of isolated cells differentiated from the human induced pluripotent stem cell line, wherein said cells exhibit a phenotype associated with the health condition or predisposition for the health condition, with a negative control agent;
(iii) assaying a phenotype in the first population and second population after the contacting steps; and
(iv) identifying the candidate agent as correcting the phenotype if the assayed phenotype of the first population after the contacting step is closer to a normal phenotype than the phenotype of the second population after the contacting step;
wherein one or more cells differentiated from the induced pluripotent stem cell line comprise an exogenous Oct3/4 gene, an exogenous Sox2 gene, and an exogenous Klf4 gene;
wherein the cells in the first and second populations of human induced pluripotent stem cells;
(a) comprise at least one endogenous allele associated with the health condition or the predisposition for the health condition;
or(b) are generated from a subject suffering from the health condition or the predisposition for the health condition.
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Abstract
The present invention involves methods for identifying an agent that corrects a phenotype associated with a health condition or a predisposition for a health condition. The invention also involves methods for identifying a diagnostic cellular phenotype, determining the risk of a health condition in a subject, methods for reducing the risk of drug toxicity in a human subject, and methods for identifying a candidate gene that contributes to a human disease. The invention also discloses human induced pluripotent stem cell lines.
139 Citations
11 Claims
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1. A method for identifying an agent that corrects a phenotype associated with a health condition or a predisposition for the health condition, comprising:
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(i) contacting a first population of isolated cells differentiated from a human induced pluripotent stem cell line, wherein said cells exhibit a phenotype associated with the health condition or predisposition for the health condition, with a candidate agent; (ii) contacting a second population of isolated cells differentiated from the human induced pluripotent stem cell line, wherein said cells exhibit a phenotype associated with the health condition or predisposition for the health condition, with a negative control agent; (iii) assaying a phenotype in the first population and second population after the contacting steps; and (iv) identifying the candidate agent as correcting the phenotype if the assayed phenotype of the first population after the contacting step is closer to a normal phenotype than the phenotype of the second population after the contacting step; wherein one or more cells differentiated from the induced pluripotent stem cell line comprise an exogenous Oct3/4 gene, an exogenous Sox2 gene, and an exogenous Klf4 gene; wherein the cells in the first and second populations of human induced pluripotent stem cells; (a) comprise at least one endogenous allele associated with the health condition or the predisposition for the health condition;
or(b) are generated from a subject suffering from the health condition or the predisposition for the health condition. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8)
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9. A method for assessing the risk of drug toxicity in a human subject, comprising:
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(i) generating iPS cells from one or more isolated somatic cells obtained from the human subject; (ii) differentiating the iPS cells obtained in step (i) to obtain one or more isolated differentiated cells; (iii) contacting one or more cells obtained in step (ii) with a dose of a pharmacological agent; (iv) assaying the contacted one or more differentiated cells for toxicity; and (v) determining that there is a low risk for toxicity if the assay is negative for toxicity in the contacted cells;
or(vi) determining that there is a high risk of toxicity if the assay is positive for toxicity in the contacted cells; wherein the differentiated cells comprise an exogenous Oct3/4 gene, an exogenous Sox2 gene and an exogenous Klf4 gene.
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10. A method for assessing the efficacy of a dose of a pharmacological agent in a human subject, comprising the steps of:
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(i) generating iPS cells from one or more isolated somatic cells obtained from the human subject; (ii) differentiating the iPS cells obtained in step (i) to obtain one or more isolated differentiated cells; (iii) contacting one or more cells obtained in step (ii) with the dose of the pharmacological agent; (iv) assaying the contacted one or more differentiated cells for a marker of efficacy of the pharmacological agent; and (v) determining that the dose of the pharmacological agent is effective if the assay is positive for efficacy in the contacted cells;
or(vi) determining that the dose of the pharmacological agent is not effective if the assay is negative for efficacy in the contacted cells; wherein the differentiated cells comprise an exogenous Oct3/4 gene, an exogenous Sox2 gene and an exogenous Klf4 gene.
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11. A method for identifying an agent that is useful as a drug, comprising the steps of:
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(i) contacting one or more isolated cells differentiated from an induced pluripotent stem cell line with a dose of a candidate agent; (ii) assaying the contacted one or more differentiated cells for desired efficacy; and (iii) identifying the candidate agent as useful if the assay is positive for efficacy in the contacted cells;
or(iv) identifying the candidate agent as not useful if the assay is negative for efficacy in the contacted cells; wherein the one or more cells differentiated from the induced pluripotent stem cell line comprise an exogenous Oct3/4 gene, an exogenous Sox2 gene, and an exogenous Klf4 gene.
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Specification