Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer
| Autor: | B Thöny, Z Ding, P Georgiev |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Male
Tail medicine.medical_specialty Phenylalanine hydroxylase Phenylalanine Genetic enhancement Genetic Vectors DNA Recombinant Mice Transgenic medicine.disease_cause Viral vector Mice Sex Factors Hyperphenylalaninemia Black hair Transduction Genetic Phenylketonurias Internal medicine Genetics medicine Animals Phenylketonuria (PKU) Hair Color Molecular Biology Adeno-associated virus biology Portal Vein Genetic transfer Antibodies Monoclonal Phenylalanine Hydroxylase Genetic Therapy Dependovirus medicine.disease Mice Inbred C57BL Endocrinology Liver Injections Intravenous Models Animal biology.protein Molecular Medicine Female |
| Zdroj: | Gene Therapy. 13:587-593 |
| ISSN: | 1476-5462 0969-7128 |
| DOI: | 10.1038/sj.gt.3302684 |
| Popis: | Phenylketonuria (PKU) is an inborn error of metabolism caused by deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) which leads to high blood phenylalanine (Phe) levels and consequent damage of the developing brain with severe mental retardation if left untreated in early infancy. The current dietary Phe restriction treatment has certain clinical limitations. To explore a long-term nondietary restriction treatment, a somatic gene transfer approach in a PKU mouse model (C57Bl/6-Pahenu2) was employed to examine its preclinical feasibility. A recombinant adeno-associated virus (rAAV) vector containing the murine Pah-cDNA was generated, pseudotyped with capsids from AAV serotype 8, and delivered into the liver of PKU mice via single intraportal or tail vein injections. The blood Phe concentrations decreased to normal levels (< or =100 microM or 1.7 mg/dl) 2 weeks after vector application, independent of the sex of the PKU animals and the route of application. In particular, the therapeutic long-term correction in females was also dramatic, which had previously been shown to be difficult to achieve. Therapeutic ranges of Phe were accompanied by the phenotypic reversion from brown to black hair. In treated mice, PAH enzyme activity in whole liver extracts reversed to normal and neither hepatic toxicity nor immunogenicity was observed. In contrast, a lentiviral vector expressing the murine Pah-cDNA, delivered via intraportal vein injection into PKU mice, did not result in therapeutic levels of blood Phe. This study demonstrates the complete correction of hyperphenylalaninemia in both males and females with a rAAV serotype 8 vector. More importantly, the feasibility of a single intravenous injection may pave the way to develop a clinical gene therapy procedure for PKU patients. |
| Databáze: | OpenAIRE |
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