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Reversal of gene expression profile in the phenylketonuria mouse model after adeno-associated virus vector-mediated gene therapy

Title
Reversal of gene expression profile in the phenylketonuria mouse model after adeno-associated virus vector-mediated gene therapy
Authors
Oh H.-J.Lee H.Park J.-W.Rhee H.Koo S.K.Kang S.Jo I.Jung S.-C.
Ewha Authors
정성철조인호박주원
SCOPUS Author ID
정성철scopus; 조인호scopus; 박주원scopus
Issue Date
2005
Journal Title
Molecular Genetics and Metabolism
ISSN
1096-7192JCR Link
Citation
vol. 86, no. SUPPL., pp. S124 - S132
Indexed
SCI; SCIE; SCOPUS WOS scopus
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 μM), 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 α 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. © 2005 Elsevier Inc. All rights reserved.
DOI
10.1016/j.ymgme.2005.06.015
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의학전문대학원 > 의학과 > Journal papers
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