Fumarylacetoacetate hydrolase (fah)-deficient pigs and uses thereof

摘要

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.

主权项

1. 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.