Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 144-153 |
| Number of pages | 10 |
| Journal | Stem Cell Research |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2014 |
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ASJC Scopus subject areas
- Cell Biology
- Developmental Biology
- Medicine(all)
Cite this
Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease. / Hickey, Raymond; Mao, Shennen A.; Glorioso, Jaime; Lillegard, Joseph B.; Fisher, James E.; Amiot, Bruce; Rinaldo, Piero; Harding, Cary O.; Marler, Ronald J; Finegold, Milton J.; Grompe, Markus; Nyberg, Scott.
In: Stem Cell Research, Vol. 13, No. 1, 2014, p. 144-153.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease
AU - Hickey, Raymond
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 J
AU - Finegold, Milton J.
AU - Grompe, Markus
AU - Nyberg, Scott
PY - 2014
Y1 - 2014
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.
UR - http://www.scopus.com/inward/record.url?scp=84901477570&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901477570&partnerID=8YFLogxK
U2 - 10.1016/j.scr.2014.05.003
DO - 10.1016/j.scr.2014.05.003
M3 - Article
C2 - 24879068
AN - SCOPUS:84901477570
VL - 13
SP - 144
EP - 153
JO - Stem Cell Research
JF - Stem Cell Research
SN - 1873-5061
IS - 1
ER -