Early gestational gene transfer with targeted ATP7B expression in the liver improves phenotype in a murine model of Wilson's disease
| Autor: | Antonetta Radu, Jessica L. Roybal, Svetlana Lutsenko, Philip W. Zoltick, Masayuki Endo, Lindsey Gray, Alan W. Flake, Carlyn A. Todorow |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Pathology medicine.medical_specialty Genetic enhancement Genetic Vectors Gene Expression Injections Andrology Mice Hepatolenticular Degeneration Liver Function Tests Genes Reporter Gene expression Genetics Transcriptional regulation medicine Animals Humans Molecular Biology Gene Cation Transport Proteins Adenosine Triphosphatases Mice Knockout biology medicine.diagnostic_test Gene Transfer Techniques Ceruloplasmin Biological Transport Genetic Therapy medicine.disease Wilson's disease Disease Models Animal Phenotype Liver In utero Copper-Transporting ATPases Organ Specificity biology.protein Molecular Medicine Female Hydroxymethylglutaryl CoA Reductases Liver function tests Copper Protein Binding |
| Zdroj: | Gene therapy. 19(11) |
| ISSN: | 1476-5462 |
| Popis: | The ideal gene therapy for metabolical liver disorders would target hepatocytes before the onset of disease and be durable, non-toxic and non-immunogenic. Early gestational gene transfer can achieve such goals. Here, we demonstrate that prenatal gene transfer of human Atp7b reduces liver pathology and improves biochemical markers in Atp7b(-/-) mice, a murine model of Wilson's disease (WD). Following prenatal injection of lentivirus vector containing the human Atp7b gene under the transcriptional control of a liver-specific promoter, the full-length ATP7B was detectable in mouse livers for the entire duration of experiments (20 weeks after birth). In contrast to a marked pathology in non-injected animals, livers from age-matched treated mice consistently demonstrated normal gross and histological morphology. Hepatic copper content was decreased in the majority of treated mice, although remaining copper levels varied. Improvement of hepatic copper metabolism was further apparent from the presence of copper-bound ceruloplasmin in the sera and normalization of the mRNA levels for HMG CoA-reductase. With this approach, the complete loss of copper transport function can be ameliorated, as evident from phenotypical improvement in treated Atp7b(-/-) mice. This study provides proof of principle for in utero gene therapy in WD and other liver-based enzyme deficiencies. |
| Databáze: | OpenAIRE |
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