期刊
GENE THERAPY
卷 13, 期 5, 页码 457-462出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3302678
关键词
phenylketonuria; phenylalanine; phenylalanine hydroxylase; adeno-associated virus; liver gene therapy; mouse model
类别
资金
- NIDDK NIH HHS [R01 DK059371-04, R01 DK059371-03A3, R01 DK059371] Funding Source: Medline
Novel recombinant adeno-associated virus vectors pseudotyped with serotype 8 capsid (rAAV2/8) have recently shown exciting promise as effective liver-directed gene transfer reagents. We have produced a novel liver-specific rAAV2/8 vector expressing the mouse phenylalanine hydroxylase (Pah) cDNA and have administered this vector to hyperphenylalaninemic PAH-deficient Pahenu2 mice, a model of human phenylketonuria (PKU). Our hypothesis was that this vector would produce sufficient hepatocyte transduction frequency and PAH activity to correct blood phenylalanine levels in murine PKU. Portal vein injection of recombinant AAV2/8 vector into five adult Pah(enu2) mice yielded complete and stable ( up to 17 weeks) correction of serum phenylalanine levels. Liver PAH activity was corrected to 11.5 +/- 2.4% of wild type liver activity and was associated with a significant increase in phenylalanine clearance following parenteral phenylalanine challenge. Although questions of long-term safety and stability of expression remain, recombinant AAV2/8-mediated, liver-directed gene therapy is a promising novel treatment approach for PKU and allied inborn errors of metabolism.
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