Gene expression profiling of Fah-deficient mouse livers upon short-term nitisinone discontinuation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE161478 | GEO | 2020/12/23
REPOSITORIES: GEO
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Project description:Hereditary tyrosinemia type 1 (HT1) is a severe genetic disorder that affects the liver due to a defective fumarylacetoacetate hydrolase (Fah) enzyme in hepatocytes. The drug nitisinone (NTBC) has offered a life-saving treatment for HT1 patients by inhibiting the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD). We used microarray analyses to define the impact of short-term (ie. seven days) NTBC therapy discontinuation on the gene expression profile of liver tissue of Fah-deficient mice. Consequently, we investigated the modulation of canonical pathways related to oxidative stress, glutathione metabolism and liver regeneration.
2023-06-03 | GSE205434 | GEO
Project description:Hereditary tyrosinemia type 1 (HT1) is a severe genetic disorder that affects the liver due to a defective fumarylacetoacetate hydrolase (Fah) enzyme in hepatocytes. The drug nitisinone (NTBC) has offered a life-saving treatment for HT1 patients by inhibiting the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD). We used microarray analyses to to identify changes in molecular pathways associated to the development and progression of the liver pathogenesis of HT1 that remain uncorrected under NTBC therapy by using gene expression profiling of Fah-deficient mouse livers subjected to continuous NTBC therapy and after seven days of NTBC therapy discontinuation. As a control of a TIMD without hepatic manifestation, we used the Hgd-deficient mouse model of AKU, also under continuous NTBC treatment and after seven days of NTBC therapy discontinuation. Consequently, we identified a set of 25 genes that discriminates HT1 livers from AKU livers, even under continuous NTBC therapy, as such representing remnants of an HT1-driven residual uncorrected liver disease phenotype.
2023-04-04 | GSE225001 | GEO
Project description:Fumarylacetoacetate hydrolase (Fah), the last enzyme of the tyrosine degradation pathway, is specifically expressed in hepatocytes in the liver. Loss of Fah leads to liver failure in mice within 6-8 weeks. This can be prevented by blocking tyrosine degradation upstream of Fah with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Here, we investigate the impact of p21 on global gene expression in Fah deficiency. Experiment Overall Design: Livers from adult wildtype, Fah or Fah, p21 knockout mice were analyzed either after continuous treatment (ON) with NTBC or after NTBC withdrawal for 14 days (OFF).
2008-06-11 | E-GEOD-11098 | biostudies-arrayexpress
Project description:Fumarylacetoacetate hydrolase (Fah), the last enzyme of the tyrosine degradation pathway, is specifically expressed in hepatocytes in the liver. Loss of Fah leads to liver failure in mice within 6-8 weeks. This can be prevented by blocking tyrosine degradation upstream of Fah with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Here, we investigate the impact of p21 on global gene expression in Fah deficiency. Keywords: treatment, genotype
2008-04-09 | GSE11098 | GEO
Project description:Conventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4- trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) delays and in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate for the first time a cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy was well tolerated and provided stable long-term expression of FAH in pigs with HT1. Genomic integration displayed a benign profile, with subsequent fibrosis and tumorigenicity gene expression patterns similar to wild-type animals as compared to NTBC-treated or diseased untreated animals. Indeed, the phenotypic and genomic data following in vivo lentiviral vector administration demonstrate comparative superiority over other therapies including ex vivo cell therapy and therefore support clinical application of this approach.
2021-11-20 | GSE189135 | GEO
Project description:Mutations in the metabolic enzyme fumarylacetoacetate hydrolase (FAH) cause hereditary tyrosinemia type I (HT1) in human. HT1 patients present acute and irreversible liver and kidney damage during infancy. CRISPR/Cas9-medated precise correction of disease-causing mutations in the liver of infant may provide a promising approach for the treatment of monogenetic liver metabolic disorders. However, to date, all previous precise gene therapy studies were conducted in adult HT1 rodent models (mice and rats), which are not able to recover irreversible pathological changes and result in less treatment effectiveness. In addition, rodent animals have very tiny livers comparing with that of humans, and HT1 rodent models do not authentically recapitulate some symptoms of human patients such as kidney damage. Therefore, to achieve the data which could be more translationable to medical practice of HT1 disease treatment by correcting gene mutation of hepatocytes, here, we chose a HT1 rabbit model, owning relatively large livers, and displaying liver and kidney damage as human patients, as the subject to test the gene therapy effectiveness starting from newborn stage. By delivery CRISPR/Cas9 system and donor templates to the livers by ear vein injection of adeno-associated virus (AAV), HT1 rabbits could be rescued the lethal phenotypes and were able to grow up to adult normally without NTBC treatment and give birth to offspring. In the livers of AAV-treated HT1 rabbits, both HDR-mediated and NHEJ-mediated gene corrections were occurred with the efficiencies ranged from 3.30% to 8.58%. Gene corrected HT1 rabbits showed normal structure and function of both livers and kidneys. This study in rabbits provides useful large-animal preclinical data to treat genetic metabolic disorders affecting the liver with gene therapy.
2019-12-31 | GSE142782 | GEO
Project description:Mutations in the metabolic enzyme fumarylacetoacetate hydrolase (FAH) cause hereditary tyrosinemia type I (HT1) in human. HT1 patients present acute and irreversible liver and kidney damage during infancy. CRISPR/Cas9-medated precise correction of disease-causing mutations in the liver of infant may provide a promising approach for the treatment of monogenetic liver metabolic disorders. However, to date, all previous precise gene therapy studies were conducted in adult HT1 rodent models (mice and rats), which are not able to recover irreversible pathological changes and result in less treatment effectiveness. In addition, rodent animals have very tiny livers comparing with that of humans, and HT1 rodent models do not authentically recapitulate some symptoms of human patients such as kidney damage. Therefore, to achieve the data which could be more translationable to medical practice of HT1 disease treatment by correcting gene mutation of hepatocytes, here, we chose a HT1 rabbit model, owning relatively large livers, and displaying liver and kidney damage as human patients, as the subject to test the gene therapy effectiveness starting from newborn stage. By delivery CRISPR/Cas9 system and donor templates to the livers by ear vein injection of adeno-associated virus (AAV), HT1 rabbits could be rescued the lethal phenotypes and were able to grow up to adult normally without NTBC treatment and give birth to offspring. In the livers of AAV-treated HT1 rabbits, both HDR-mediated and NHEJ-mediated gene corrections were occurred with the efficiencies ranged from 3.30% to 8.58%. Gene corrected HT1 rabbits showed normal structure and function of both livers and kidneys. This study in rabbits provides useful large-animal preclinical data to treat genetic metabolic disorders affecting the liver with gene therapy.
2019-12-31 | GSE142704 | GEO
Project description:Mutations in the metabolic enzyme fumarylacetoacetate hydrolase (FAH) cause hereditary tyrosinemia type I (HT1) in human. HT1 patients present acute and irreversible liver and kidney damage during infancy. CRISPR/Cas9-medated precise correction of disease-causing mutations in the liver of infant may provide a promising approach for the treatment of monogenetic liver metabolic disorders. However, to date, all previous precise gene therapy studies were conducted in adult HT1 rodent models (mice and rats), which are not able to recover irreversible pathological changes and result in less treatment effectiveness. In addition, rodent animals have very tiny livers comparing with that of humans, and HT1 rodent models do not authentically recapitulate some symptoms of human patients such as kidney damage. Therefore, to achieve the data which could be more translationable to medical practice of HT1 disease treatment by correcting gene mutation of hepatocytes, here, we chose a HT1 rabbit model, owning relatively large livers, and displaying liver and kidney damage as human patients, as the subject to test the gene therapy effectiveness starting from newborn stage. By delivery CRISPR/Cas9 system and donor templates to the livers by ear vein injection of adeno-associated virus (AAV), HT1 rabbits could be rescued the lethal phenotypes and were able to grow up to adult normally without NTBC treatment and give birth to offspring. In the livers of AAV-treated HT1 rabbits, both HDR-mediated and NHEJ-mediated gene corrections were occurred with the efficiencies ranged from 3.30% to 8.58%. Gene corrected HT1 rabbits showed normal structure and function of both livers and kidneys. This study in rabbits provides useful large-animal preclinical data to treat genetic metabolic disorders affecting the liver with gene therapy.
2019-12-31 | GSE142722 | GEO
Project description:Mutations in the metabolic enzyme fumarylacetoacetate hydrolase (FAH) cause hereditary tyrosinemia type I (HT1) in human. HT1 patients present acute and irreversible liver and kidney damage during infancy. CRISPR/Cas9-medated precise correction of disease-causing mutations in the liver of infant may provide a promising approach for the treatment of monogenetic liver metabolic disorders. However, to date, all previous precise gene therapy studies were conducted in adult HT1 rodent models (mice and rats), which are not able to recover irreversible pathological changes and result in less treatment effectiveness. In addition, rodent animals have very tiny livers comparing with that of humans, and HT1 rodent models do not authentically recapitulate some symptoms of human patients such as kidney damage. Therefore, to achieve the data which could be more translationable to medical practice of HT1 disease treatment by correcting gene mutation of hepatocytes, here, we chose a HT1 rabbit model, owning relatively large livers, and displaying liver and kidney damage as human patients, as the subject to test the gene therapy effectiveness starting from newborn stage. By delivery CRISPR/Cas9 system and donor templates to the livers by ear vein injection of adeno-associated virus (AAV), HT1 rabbits could be rescued the lethal phenotypes and were able to grow up to adult normally without NTBC treatment and give birth to offspring. In the livers of AAV-treated HT1 rabbits, both HDR-mediated and NHEJ-mediated gene corrections were occurred with the efficiencies ranged from 3.30% to 8.58%. Gene corrected HT1 rabbits showed normal structure and function of both livers and kidneys. This study in rabbits provides useful large-animal preclinical data to treat genetic metabolic disorders affecting the liver with gene therapy.
2019-12-31 | GSE142721 | GEO
Project description:Reprogramming metabolism plays an important role in tumor cells for maintaining their abnormal biologic behaviors. Therefore, special factors could regulate metabolic processes and influence the overall status of tumor cells. This phenomenon was obviously found in melanoma. Fumarylacetoacetate hydrolase (fumarylacetoacetase, FAH) is an enzyme encoded by the FAH gene located on the chromosome 15q25.1 region and contains 14 exons. FAH enzyme catalyzes the hydrolysis of 4- fumarylacetoacetase into fumarate and acetoacetate. It is the last enzyme in the subpathway from L-phenylalanine and tyrosine degradation. Mutations in the FAH gene cause type I tyrosinemia, which is a hereditary error of metabolism that is characterized by increased tyrosine levels in the blood and urine of patients. In the present study, we will explore whether FAH is an essential enzyme to promote multiple metabolic processes and elucidate the functions of FAH in melanoma. Gene microarrays and bioinformatics analysis of the differentially expressed genes (DEGs) were performed using A375 cells, and we concentrated on the biologic functions of FAH. In general, our work revealed several functional mechanisms of FAH in melanoma, which indicated FAH might be a potentially therapeutic target and an independent prognostic indicator for this disease.
2018-02-14 | GSE86870 | GEO