title: Reversal of gene expression profile in the phenylketonuria mouse model after adeno-associated virus vector-mediated gene therapy.
abstract: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by phenylalanine hydroxylase (PAH) deficiency. Accumulation of phenylalanine leads to severe mental and psychomotor retardation, and hypopigmentation of skin and hair. We have demonstrated the cognitive outcome of biochemical and phenotypic reversal by the adeno-associated virus vector-mediated gene delivery of a human PAH transgene. In this study, we identified the expression of genes related to pathologic abnormalities of the PKU-affected brain, in which the symptoms of PKU are mainly manifest, and transcriptional changes in effective gene therapy treatment using oligonucleotide array. Therapeutic effectiveness was verified by change in enzyme activity (15+/-5.84%), phenylalanine plasma level (261+/-108 microM), and coat color. Our data indicated that 12 genes were significantly up-regulated in PKU. Four are involved in defense and inflammatory responses of neutrophils (NE, MPO, NGP, and CRAMP), three other overexpressed genes are related to extracellular matrix organization and degradation (COL1A1, COL1A2, and MMP13); the remainder were a nociceptor in sensory neurons (MrgA1), a structural gene of P lysozyme (Lzp-s), an immunoglobulin alpha heavy chain constant region gene (Igh-2), an osteocalcin-related protein precursor (Bglap-rs1), and a membrane-spanning 4 domain, subfamily A, member 3 (Ms4a3). Data demonstrated that elevated genes in the PKU-affected brain could be normalized by human PAH gene delivery. Although we could not precisely link transcript level changes and neurologic pathogenesis, this study provides a more comprehensive understanding of the PKU-affected brain at the molecular level, possibly resulting in better therapeutic approaches.
authors.affiliation: Department of Biomedical Sciences, National Institute of Health, Seoul 122-701, Republic of Korea.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Oh
authors.forename: Hyejin
authors.initials: H
authors.lastname: Lee
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Hwanseok
authors.initials: H
authors.lastname: Rhee
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Koo
authors.forename: Seongman
authors.initials: S
authors.lastname: Kang
authors.forename: Inho
authors.initials: I
authors.lastname: Jo
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Jung
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D010649:Phenylalanine / Q000378:metabolism*; D010651:Phenylalanine Hydroxylase / Q000172:deficiency / Q000235:genetics; D010661:Phenylketonurias / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D019076:Transgenes; D015854:Up-Regulation
chemical_list: D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase