TY - JOUR
T1 - Reversal of gene expression profile in the phenylketonuria mouse model after adeno-associated virus vector-mediated gene therapy
AU - Oh, Hyun Jeong
AU - Lee, Hyejin
AU - Park, Joo Won
AU - Rhee, Hwanseok
AU - Koo, Soo Kyung
AU - Kang, Seongman
AU - Jo, Inho
AU - Jung, Sung Chul
N1 - Funding Information:
This study was supported by a grant of the Korea 21 R&D Project (01-PJ10-PG6-01GN15-0001), from the Ministry of Health and Welfare, Republic of Korea.
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
KW - Adeno-associated virus
KW - Gene therapy
KW - Microarray
KW - Mouse
KW - Neurological pathogenesis
KW - Phenylketonuria
UR - http://www.scopus.com/inward/record.url?scp=28844474908&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2005.06.015
DO - 10.1016/j.ymgme.2005.06.015
M3 - Article
C2 - 16150627
AN - SCOPUS:28844474908
SN - 1096-7192
VL - 86
SP - 124
EP - 132
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - SUPPL.
ER -