Propagation of human hepatocytes in non-human animals
First Claim
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1. A non-human animal having a liver that comprises human hepatocytes, wherein the animal has a normal immune system but has been rendered tolerant to human hepatocytes.
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Abstract
The present invention relates to the preparation of non-human animals having chimeric livers, whereby some or substantially all of the hepatocytes present are human hepatocytes. It is based, at least in part, on the discovery that rats, tolerized in utero against human hepatocytes, were found to serve as long-term hosts for human hepatocytes introduced post-natally, and the introduced hepatocytes maintained their differentiated phenotype, as evidenced by continued production of human albumin.
6 Citations
46 Claims
- 1. A non-human animal having a liver that comprises human hepatocytes, wherein the animal has a normal immune system but has been rendered tolerant to human hepatocytes.
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9. A method of preparing a non-human animal having a liver comprising human hepatocytes, comprising the steps of:
- (i) inducing tolerance in a non-human host animal toward hepatocytes from a human donor and (ii) introducing hepatocytes from the human donor into the tolerized animal produced in step (i) such that at least some of the introduced human hepatocytes localize in the liver of the non-human animal.
- View Dependent Claims (10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
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20. A method for identifying a toxic effect of a test agent, comprising administering the test agent to a non-human animal having a liver that comprises human hepatocytes and subsequently evaluating whether changes have occurred in at least one marker of bodily function of the animal.
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21. A method for identifying a toxic effect of a test agent, comprising administering the test agent to a non-human animal having a liver that comprises human hepatocytes and subsequently evaluating whether changes have occurred in the viability of human hepatocytes in the animal.
- 22. A model system for a human liver disease comprising a non-human animal having a liver that comprises human hepatocytes in which an agent associated with causation of the disease in humans has been introduced.
- 24. A model system for a human liver disease caused by an infectious agent, comprising a non-human animal having a liver that comprises human hepatocytes infected by the infectious agent.
- 34. A model system for a human liver disease caused by a virus, comprising a non-human animal having a liver that comprises human hepatocytes containing a nucleic acid of the virus, where the nucleic acid is selected from the group consisting of a nucleic acid comprised in the genome of the virus and a nucleic acid transcript encoded by the genome of the virus.
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43. A method of treating a human subject having a genetic defect, comprising (i) propagating human hepatocytes that correct the genetic defect in a non-human animal, where the human hepatocytes are histocompatible with the human subject;
- (ii) collecting hepatocytes from the animal;
(iii) separating human hepatocytes from non-human hepatocytes; and
(iv) introducing the human hepatocytes into the subject. - View Dependent Claims (44)
- (ii) collecting hepatocytes from the animal;
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45. A method of treating a human subject having a damaged liver, comprising (i) propagating human hepatocytes in a non-human animal, where the human hepatocytes are histocompatible with the human subject;
- (ii) collecting hepatocytes from the animal;
(iii) separating human hepatocytes from non-human hepatocytes; and
(iv) introducing the human hepatocytes into the subject. - View Dependent Claims (46)
- (ii) collecting hepatocytes from the animal;
Specification