Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2004-04-01

AUTHORS

S Mochizuki, H Mizukami, T Ogura, S Kure, A Ichinohe, K Kojima, Y Matsubara, E Kobayahi, T Okada, A Hoshika, K Ozawa, A Kume

ABSTRACT

Classical phenylketonuria (PKU) is a metabolic disorder caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). If untreated, accumulation of phenylalanine will damage the developing brain of affected individuals, leading to severe mental retardation. Here, we show that a liver-directed PAH gene transfer brought about long-term correction of hyperphenylalaninemia and behavioral improvement in a mouse model of PKU. A recombinant adeno-associated virus (AAV) vector carrying the murine PAH cDNA was constructed and administered to PAH-deficient mice (strain PAHenu2) via the portal vein. Within 2 weeks of treatment, the hyperphenylalaninemic phenotype improved and completely normalized in the animals treated with higher vector doses. The therapeutic effect persisted for 40 weeks in male mice, while serum phenylalanine concentrations in female animals gradually returned to pretreatment levels. Notably, this long-term correction of hyperphenylalaninemia was associated with a reversal of hypoactivity observed in PAHenu2 mice. While locomotory activity over 24 h and exploratory behavior were significantly decreased in untreated PAHenu2 mice compared with the age-matched controls, these indices were completely normalized in 12-month-old male PKU mice with lowered serum phenylalanine. These results demonstrate that AAV-mediated liver transduction ameliorated the PKU phenotype, including central nervous system dysfunctions. More... »

PAGES

1081-1086

Journal

TITLE

Gene Therapy

ISSUE

13

VOLUME

11

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.gt.3302262

DOI

http://dx.doi.org/10.1038/sj.gt.3302262

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/15057263


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51 brain
52 cDNA
53 central nervous system dysfunction
54 classical phenylketonuria
55 concentration
56 control
57 correction
58 deficiency
59 disorders
60 doses
61 dysfunction
62 effect
63 enzyme phenylalanine hydroxylase
64 exploratory behavior
65 female animals
66 gene transfer
67 hepatic enzyme phenylalanine hydroxylase
68 high vector doses
69 hydroxylase
70 hyperphenylalaninemia
71 hypoactivity
72 improvement
73 index
74 individuals
75 levels
76 liver transduction
77 locomotory activity
78 long-term correction
79 male mice
80 mental retardation
81 metabolic disorders
82 mice
83 model
84 mouse model
85 nervous system dysfunction
86 phenotype
87 phenylalanine
88 phenylalanine concentrations
89 phenylalanine hydroxylase
90 phenylketonuria
91 phenylketonuria mice
92 portal vein
93 pretreatment levels
94 recovery
95 results
96 retardation
97 reversal
98 serum phenylalanine
99 serum phenylalanine concentration
100 severe mental retardation
101 system dysfunction
102 therapeutic effect
103 transduction
104 transfer
105 treatment
106 vector
107 vector doses
108 vein
109 virus vectors
110 weeks
111 weeks of treatment
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