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US 9,000,257 B2Granted
Fumarylacetoacetate hydrolase (fah)-deficient pigs and uses thereof
AssigneesOregon Health & Science University, Mayo Foundation for Medical Education and Research
InventorsMarkus Grompe, Scott Nyberg, Joseph Lillegard, Raymond Hickey
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Abstract
Described herein is the generation of Fah+/− heterozygote pigs by homologous recombination and somatic cell nuclear transfer, and a method for producing Fah−/− homozygote pigs. The Fah-deficient pigs of the disclosure can be used for a variety of research and therapeutic purposes, such as for the expansion of human hepatocytes, and as large animal models of hereditary tyrosinemia type 1, cirrhosis and hepatocellular carcinoma.
Claims15
A method of expanding human hepatocytes in vivo, comprising:
- (i) transplanting human hepatocytes or human hepatocyte precursor cells into a Fah-deficient pig, wherein the Fah-deficient pig is administered 2-(2-nitro-4-trifluoro-methyl-benzoyl)-1,3 cyclohexanedione (NTBC) prior to transplantation at a dose sufficient to prevent liver dysfunction, and allowing the human hepatocytes to expand;
- or (ii) transplanting human hepatocytes or human hepatocyte precursor cells into a Fah-deficient pig fetus of a pregnant sow, wherein the sow pregnant with the Fah-deficient pig fetus is administered NTBC, and allowing the human hepatocytes to expand following birth of the Fah-deficient pig,
- wherein the Fah-deficient pig or pig fetus comprises homozygous disruptions in the Fah gene such that the disruption results in loss of expression of functional FAH protein, thereby expanding the human hepatocytes.
Dependencies are inferred from the claim text.