In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA781617 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16975863_1.fastq.gz | Fastqsanger.gz | |||
| SRR16975863_2.fastq.gz | Fastqsanger.gz | |||
| SRR16975864_1.fastq.gz | Fastqsanger.gz | |||
| SRR16975864_2.fastq.gz | Fastqsanger.gz | |||
| SRR16975865_1.fastq.gz | Fastqsanger.gz |
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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: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 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 is well tolerated and provides stable long-term expression of FAH in pigs with HT1. Genomic integration displays 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.
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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.
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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.
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