• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Gene therapy of urea cycle deficirncy

Research Project

Project/Area Number 06454610
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Human genetics
Research InstitutionKumamoto University

Principal Investigator

MATSUDA Ichiro  Kumamoto University School of Medicine Department of Pediatrics Professor, 医学部, 教授 (10000986)

Co-Investigator(Kenkyū-buntansha) SAITO Izumu  The University of Tokyo The Institute of Medical Science Laboratory of Molecular, 医科学研究所, 助教授 (70158913)
INDO Yasuhiro  Kumamoto University School of Medicine Department of Hospital Assistant Professo, 医学部・附属病院, 助手 (40244131)
ENDO Fumio  Kumamoto University School of Medicine Department of Hospital Lecturer, 医学部・附属病院, 講師 (00176801)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 1995: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1994: ¥4,400,000 (Direct Cost: ¥4,400,000)
KeywordsGene therapy / Urea cycle / Ornithine transcarbamylase / Adenovirus vector / OTC欠損症 / CAGプロモーター / spf^<ash>マウス
Research Abstract

Ornithine transcarbamylase (OTC) deficiency, the most commom and severe inborn error of the urea cycle in humans, remains without adequate treatment, and ortality rates are high. Adenoviral vectors provide an efficient system for gene delivery, but there are problems, including toxicity. Efficient promoters that reduce the amount of vector required for treatment need to be developed. We constructed two recombinant adenoviral vectors, AdexCAGhOTC and AdexSRalphahOTC,which harbor the human OTC gene under transcriptional control of CAG (a modified chicken beta-actin promoter with CMV-IE enhancer) and SRalpha (the SV 40 early prommoter with the R segment and part of the U5 segment of the HTLV-1 LTR) , respectively. Each was tested in adult spf^<ash> mice, an animal model of human OTC deficiency, and in primary human hepatocytes with OTC deficiency. Spf^<ash> mice have a pronounced orotic aciduria as seen in humans. A complete recovery of hepatic OTC activity with minimal tissue damage was observed in these animals following the intravenous administration of AdexCAGhOTC alone. Western blot analysis confirmed hepatic OTC expression and normalization of orotic aciduria was evident for 60 days. Enzyme activities of primary human hepatocytes infected with AdexCAGhOTC were 10-40 times higher than those with AdexSRalphahOTC.Thus, the adenoviral vector with an efficient promoter such as CAG,can be given further considerartion for possible gene therapy in humans with OTC deficiency.

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Matsuda I.,et al.: "Ultrastructural, immunocytochemical and stereological investigation of hepatocytes in a patients with mutation of ornithine transcarbamylase gene." Eup. J Cell Biolog.67. 73-83 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsuda I.,et al.: "Assignment of the human carbamylphosphate synthetase 1 gene to 2q35 by flouoressence in situ hybridization." Genomics.28. 124-125 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsuda I.,et al.: "Molecular basisi of clinical response to dietary treatment in patients with argininemia." Human Genet.96. 250-260 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsuda I.,et al.: "Proportions of spontaneons mutations in males and femaler with ornithine transcarbamylase deficiency." Am. J. Med. Genet.55. 67-70 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Endo F.,et al.: "A nonsense mutation in the 4-hydroxyphenylpyruvic acid dioxyphenylpyruvic acid dioxygenase gene causes skipping of the constitutive exon and hypertyrosinemia in mouse stration III." Genomics. 25. 164-169 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Saito I.,et al.: "Neural cell type specific expression system using recombinant adenovirus vectors." Hum. Gene. Ther.(in press). (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsuda Ichiro., et al.: "Ultrastructural, immunocytochemical and stereologicak investigation of hepatocytes in a patients with mutation of ornithine transcarbamylase gene." Eurp.J.Cell Biolog.67. 73-83 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsuda Ichiro, et.al.: "Assignment of the human carbamylphosphate synthetase l gene to 2q35 by flouoressence in situ hybridization" Genomics. 28. 124-125 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsuda Ichiro, et.al.: "Molecular basis of clinical response to dietary treatment in patients with argininemia." Human Genet.96. 250-260 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsuda Ichiro, et.al.: "Proportions of spontaneons mutations in males and femaler with ornithine transcarbamylase deficiency." Am.J.Med.Genet.55. 67-70 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] "A nonsense mutation in the 4-hydroxyphenylpyruvic acid dioxyphenylpyruvic acid dioxygenase gene causes skipping of the constitutive exon and hypertyrosinemia in mouse stration III" Genomics. 25. 164-169 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] "Neural cell type specific expression system using recombinant adenovirus vectors." Hum.Gene.Ther.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsuda I.,et al.: "Ultrastructural,immunocytochemical and stereological investigation of hepatocytes in a patients with mutation of ornithine transcarbamylase gene." Eup.J Cell Biolog.67. 73-83 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Assignment of the human carbamylphosphate synthetase 1 gene to 2q35 by flouoressence in situ hybridization." Genomics.28. 124-125 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Molecular basisi of clinical response to dietary treatment in patients with argininemia." Human Genet.96. 250-260 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Proportions of spontaneons mutations in males and femaler with ornithine transcarbamylase deficiency." Am.J.Med.Genet.55. 67-70 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Endo F.,et al.: "A nonsense mutation in the 4-hydroxyphenylpyruvic acid dioxyphenylpyruvic acid dioxygenase gene causes skipping of the constitutive exon and hypertyrosinemia in mouse stration III." Genomics. 25. 164-169 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Saito I.,et al.: "Neural cell type specific expression system using recombinant adenovirus vectors." Hum.Gene.Ther.(in press). (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Matusda I.,et al.: "Zine supplementation inproves the conversion of T4 to T3 in disabled patients with zinc deficiency." J.Am.Coll.Nutr.13. 62-67 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Expression of four mutant human ornithine transcarbamylase genes in cultured Cos 1 cells related to clinical phenotypes." Human Genet.93. 129-134 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Deficiency of the Elb subunit in the branched-chain α-keto acid dehydrogenase complex due to a single base substitution of the intron 5,resulting in two alternatively spliced mRNA in a patient with maple syrup urine disease." Biochim.Biophys.Acta.1225. 317-325 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Characterization of a point mutation in the pyruvate dehydrogenase El α gene from two boys with primary lactic acidemia." J.Inh.Metab.Dis.17. 189-195 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Four newly identified ornithine transcarbamylase (OTC) mutation (D126G,R129H,I172M and W332X) in Japanese male patients with early onset OTC deficiency." Human Mutation. 3. 402-406 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et.al.: "Homologous dinucleotide (GT or TG) deletion in Japanese patients with chronic granulomatous disease with p47-phox deficiency." Biochim.Biophys.Res.Comm.199. 1372-1377 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Structural organization and analysis of the human fumarylacetoacetatehydlase gene in tyrosinemia type I." Biochim.Biophys.Acta.1220. 168-172 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et.al.: "Structure of the human 4-hydroxy phenylpyruvic acid dehydrogenase gene." Genomics.23. 534-539 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Mutation in CoL 4A5 gene in alport syndrome : A possible mutation in primodial gern cells." Kidney Int.46. 1307-1317 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et al.: "The rat argininosuccinate lyase promoter : The dyad-symmetric CCAAT box sequence CCAATTGG in the promoter is recognized by NF-Y." J.Biochem.116. 1044-1055 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Measurement of blood holoceruloplasmin by El α using a mouse monoclonal antibody directed to holoceruloplasmin. Implication for mass screaning." J.Inh.Metab.Dis.17. 616-620 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsuda I.,et al.: "Molecular analysis for the diagnosis of X-linked hyper-IgM syndrome." Biochem.Biophys.Acta.1260. 62-67 (1995)

    • Related Report
      1994 Annual Research Report

URL: 

Published: 1994-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi