TY - JOUR
T1 - Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease
AU - Hickey, Raymond D.
AU - Mao, Shennen A.
AU - Glorioso, Jaime
AU - Lillegard, Joseph B.
AU - Fisher, James E.
AU - Amiot, Bruce
AU - Rinaldo, Piero
AU - Harding, Cary O.
AU - Marler, Ronald
AU - Finegold, Milton J.
AU - Grompe, Markus
AU - Nyberg, Scott L.
N1 - Funding Information:
We thank Angela Major of the NIDDK -sponsored Digestive Disease Core Laboratory of the Texas Medical Center ( DK56338 ), LouAnn Gross (Mayo Clinic, Rochester) and Jenny Pattengill (Mayo Clinic, Arizona) for histology support. We thank Denise Rokke (Mayo Clinic, Rochester) for elemental analysis. We thank John Bial and Yecuris INC for financial support of early studies involving FAH deficient pigs.
Funding Information:
Financial support: S. Nyberg was funded by the National Institutes of Health (grant R01-DK56733 and R41 DK092105 ), the Marriott Foundation, the Wallace H. Coulter Foundation , the American Society of Transplant Surgeons/Pfizer Collaborative Scientist Grant, and the American Society of Transplant Surgeons/National Kidney Foundation Folkert Belzer Award. M. Grompe was supported by the National Institutes of Health (grant DK048252 ).
PY - 2014/7
Y1 - 2014/7
N2 - Hereditary tyrosinemia type I (HT1) is caused by deficiency in fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the last step of tyrosine metabolism. The most severe form of the disease presents acutely during infancy, and is characterized by severe liver involvement, most commonly resulting in death if untreated. Generation of FAH+/- pigs was previously accomplished by adeno-associated virus-mediated gene knockout in fibroblasts and somatic cell nuclear transfer. Subsequently, these animals were outbred and crossed to produce the first FAH-/- pigs.FAH-deficiency produced a lethal defect in utero that was corrected by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione (NTBC) throughout pregnancy. Animals on NTBC were phenotypically normal at birth; however, the animals were euthanized approximately four weeks after withdrawal of NTBC due to clinical decline and physical examination findings of severe liver injury and encephalopathy consistent with acute liver failure. Biochemical and histological analyses, characterized by diffuse and severe hepatocellular damage, confirmed the diagnosis of severe liver injury. FAH-/- pigs provide the first genetically engineered large animal model of a metabolic liver disorder. Future applications of FAH-/- pigs include discovery research as a large animal model of HT1 and spontaneous acute liver failure, and preclinical testing of the efficacy of liver cell therapies, including transplantation of hepatocytes, liver stem cells, and pluripotent stem cell-derived hepatocytes.
AB - Hereditary tyrosinemia type I (HT1) is caused by deficiency in fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the last step of tyrosine metabolism. The most severe form of the disease presents acutely during infancy, and is characterized by severe liver involvement, most commonly resulting in death if untreated. Generation of FAH+/- pigs was previously accomplished by adeno-associated virus-mediated gene knockout in fibroblasts and somatic cell nuclear transfer. Subsequently, these animals were outbred and crossed to produce the first FAH-/- pigs.FAH-deficiency produced a lethal defect in utero that was corrected by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione (NTBC) throughout pregnancy. Animals on NTBC were phenotypically normal at birth; however, the animals were euthanized approximately four weeks after withdrawal of NTBC due to clinical decline and physical examination findings of severe liver injury and encephalopathy consistent with acute liver failure. Biochemical and histological analyses, characterized by diffuse and severe hepatocellular damage, confirmed the diagnosis of severe liver injury. FAH-/- pigs provide the first genetically engineered large animal model of a metabolic liver disorder. Future applications of FAH-/- pigs include discovery research as a large animal model of HT1 and spontaneous acute liver failure, and preclinical testing of the efficacy of liver cell therapies, including transplantation of hepatocytes, liver stem cells, and pluripotent stem cell-derived hepatocytes.
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U2 - 10.1016/j.scr.2014.05.003
DO - 10.1016/j.scr.2014.05.003
M3 - Article
C2 - 24879068
AN - SCOPUS:84901477570
SN - 1873-5061
VL - 13
SP - 144
EP - 153
JO - Stem Cell Research
JF - Stem Cell Research
IS - 1
ER -