2000 Fiscal Year Final Research Report Summary
GENE THERAPY IN PHENYLKETONURIA
| Project/Area Number |
11670736
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
MATSUBARA Yoichi TOHOKU UNIV, MEDICAL GENETICS, PROFESSOR, 大学院・医学系研究科, 教授 (00209602)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Yoichi TOHOKU UNIV, MEDICAL GENETICS, ASSOCIATE RESEARCHER, 大学院・医学系研究科, 助手 (80216457)
KURE Shigeo TOHOKU UNIV, MEDICAL GENETICS, ASSOCIATE PROFESSOR, 大学院・医学系研究科, 助教授 (10205221)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Phenylketonuria / Gene therapy / Adenovirus / TaqMan-PCR / Tetrahydrobiopterin / Fetal gene therapy |
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| Research Abstract |
We first tested the feasibility of targeted gene correction using chimeric DNA/RNA oligonucleotide in phenylketonuria mutations. However, we failed to observe efficient nucleotide substitution as reported by Kimeragen in U.S.A.Although it seems important to characterize various parameters affecting mismatch repair mechanism and further optimize the method, our observation as well as other's might throw doubt upon the credibility of the previous reports.
In contrast, gene transfer experiments using recombinant adenovirus obtained following fruitful results : 1) a strong host immune reaction was demonstrated against extrinsic phenylalanine hydroxylase, rather than adenovirus per se ; 2) a pharmacological dose of tetrahydrobiopterin, a cofactor for phenylalanine hydroxylase, appeared to enhance the enzymatic activity after gene therapy ; 3) an efficient gene transfer method to fetus was established in an animal model ; 4) a TaqMan-PCR method to quantify adenoviral particles in tissues was developed. Our study will facilitate the clinical application of gene therapy in inborn errors of metabolism caused by hepatic enzyme deficiency.
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Research Products
(26 results)
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[Publications] Nagasaki, Y., Matsubara, Y., Takano, H., Fujii, K., Senoo, M., Akanuma, J., Takahashi, K., Kure, S., Hara, M., Kanegae, Y., Saito, I., and Narisawa, K.: "Reversal of hypopigmentation in phenylketonuria model mice by adenovirus-mediated gene transfer."Pediatr. Res.. 45. 465-473 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Asanuma, A., Ohura, T., Ogawa, E., Sato, S., Igarashi, Y., Matsubara, Y., and Iinuma, K.: "Molecular analysis of Japanese patients deficient for steroid 21-hydroxylase."J.Hum. Genet.. 44. 312-317 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Kure, S., Rolland, M.-O., Leisti, J., Mandel, H., Sakata, Y., Tada, K., Matsubara, Y., and Narisawa, K.: "Prenatal diagnosis of non-ketotic hyperglycinaemia : enzymatic diagnosis in 28 families and DNA diagnosis detecting prevalent Finnish and Israeli-Arab mutations."Prenat. Diagn.. 19. 717-720 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Hou, D.-C., Kure, S., Suzuki, Y., Hasegawa, Y., Hara, Y., Inoue, T., Kida, Y., Matsubara, Y., and Narisawa, K.: "Glycogen storage disease type Ib : structural and mutational analysis of the microsomal glucose-6-phosphatase transporter gene."Am. J.Med. Genet.. 86. 253-257 (1999)
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[Publications] Kure, S., Hou D.-C., Ohura, T., Iwamoto, H., Suzuki, S., Sugiyama, N., Sakamoto, O., Fujii, K., Matsubara, Y., and Narisawa, K.: "Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency."J.Pediatr.. 135. 375-378 (1999)
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[Publications] Kudo, T., Ikeda, K., Kure, S., Matsubara, Y., Oshima, T., Watanabe, K., Kawase, T., Narisawa, K., and Takasaka, T.: "Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population."Am. J.Med. Genet.. 90. 141-145 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Fujii, K., Matsubara, Y., Akanuma, J., Takahashi, K., Kure, S., Suzuki, Y., Imaizumi, M., Iinuma, K., Sakatsume, O., Rinaldo, P., and Narisawa, K.: "Mutation detection by TaqMan-allele specific amplification : application to molecular diagnosis of glycogen storage disease type Ia and medium-chain acyl-CoA dehydrogenase deficiency."Hum. Mutat.. 15. 189-196 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Takayanagi, M., Kure, S., Sakata, Y., Kurihara, Y., Ohya, Y., Kajita, M., Tada, K., Matsubara, Y., Narisawa, K.: "Human glycine decarboxylase gene (GLDC) and its highly conserved processed pseudogene (yGLDC) : their structure and expression, and the identification of a large deletion in a family with nonketotic hyperglycinemia."Hum. Genet.. 106. 298-305 (2000)
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[Publications] Akanuma, J., Nishigaki, T., Fujii, K., Matsubara, Y., Inui, K., Takahashi, K., Kure, S., Suzuki, Y., Ohura, T., Miyabayashi, S., Ogawa, E., Iinuma, K., Okada, S., and Narisawa, K.: "Molecular diagnosis of 51 Japanese patients with glycogen storage disease type Ia : characterization of splicing mutations by analysis of ectopically transcribed mRNA from lymphoblast."Am. J.Med. Genet.. 91. 107-112 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Takahashi, K., Akanuma, J., Matsubara, T., Fujii, K., Kure, S., Suzuki, Y., Wataya, K., Sakamoto, O., Aoki, Y., Ogasawara, M., Ohura, T., Miyabayashi, S., and Narisawa, K.: "Heterogeneity of mutations in the glucose-6-phosphatase gene in Japanese patients with glycogen storage disease type Ia."Am. J.Med. Genet.. 92. 90-94 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Mizugaki, M., Hiratsuka, M., Agatsuma, Y., Matsubara, Y., Fujii, K., Kure, S., Narisawa, K.: "Rapid detection of CYP2C18 genotypes by real-time fluorescence polymerase chain reaction."J.Pharm. Pharmacol.. 52. 199-205 (2000)
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[Publications] Kure, S., Hou, D.-C., Suzuki, Y., Yamagishi, A., Hiratsuka, M., Fukuda, T., Sugie, H., Kondo, N., Matsubara, Y., and Narisawa, K.: "Glycogen storage disease type Ib without neutropenia."J.Pediatr.. 137. 253-256 (2000)
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[Publications] Senoo, M., Matsubara, Y., Fujii, K., Nagasaki, Y., Hiratsuka, M., Kure, S., Uehara, S., Okamura, K., Yajima, A., and Narisawa, K.: "Adenovirus-mediated in utero gene transfer in mice and guinea pigs : tissue distribution of recombinant adenovirus determined by quantitative TaqMan-polymerase chain reaction assay."Mol. Genet. Metab.. 69. 269-276 (2000)
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[Publications] Sakamoto, O., Ogawa, E., Ohura, T., Igarashi, Y., Matsubara, Y., Narisawa, K., Iinuma, K.: "Mutation analysis of GLUT2 gene in patients with Fanconi-Bickel syndrome."Pediatr. Res.. 48. 586-589 (2000)
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[Publications] Yang, X., Aoki, Y., Li, X., Sakamoto, O., Hiratsuka, M., Gibson, K.M., Kure, S., Narisawa, K., Matsubatra, Y., Suzuki, Y.: "Haplotype analysis suggests that the two predominant mutations in Japanese patients with holocarboxylase synthetase deficiency are founder mutations."J.Hum. Genet.. 45. 358-362 (2000)
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