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Gene Therapy for ALS with mutant SOD1 by ribozyme and catalytic DNA.

Research Project

Project/Area Number 14570582
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

YOKOTA Takanori  Tokyo Medical and Dental University, Neurology, RESEARCH ASSOCIATE, 医学部附属病院, 講師 (90231688)

Co-Investigator(Kenkyū-buntansha) MIZUSAWA Hidehiro  Tokyo Medical and Dental University, Neurology, Professor, 大学院・医歯学総合研究科, 教授 (30144091)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
KeywordssiRNA / RNAi / Gene therapy / SOD1 / ribozyme / catalyticDNA / virus vector / ウイルスベクター / DNAエンザイム / SODI / カタリテックDNA / アデノウイルスベクター / G93Aトランスジェニックマウス / SOD / 筋萎縮性側索硬化症
Research Abstract

Recently, short interfering RNA (siRNA) has been found to cleave efficiently RNA, so that we compared its efficiency for the supprresion of expression of target gene with ribozyme and catalytic DNA. In culture cells the siRNA designed for wild-type SOD1 was much more efficient to suppress the expression of SOD1 than ribozyme and catalytic DNA. When single nucleotide alternation was positioned at 9-13th nucleotide from 5' side in the sense sequence of siRNA, it can recognize a single nucleotide alternation. Using this principle, we succeeded in making the siRNA which specifically suppress the expression of mutant G93A SOD1 without influencing that of the wild-type SOD1.
For the efficient delivery of siRNA to neurons, development of the virus vectors might be necessary. First, excellent siRNA-expressing DNA vector was constructed when the U6 promotor and the stem-loop sequence of siRNA were used. Second, with this expression cassette, we successfully made siRNA-expressing adnovirus and adno-associate virus vectors. Therefore, we finish the first step of the gene therapy for ALS with mutant SOD1.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Yokota T, et al.: "Inhibition of intracellular hepatitis C Virus replication by synthetic and vector-derived small interfering RNAs"EMBO rep. 4(6). 602-608 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nishiwaki Y, Yokota T, et al.: "Introduction of short interfering RNA to silence endogenous E-selectin in vascular endothelium leads to successful inhibition of leukocyte adhesion."Biochem Biophys Res Com. 310. 1062-1066 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yokota T, et al.: "Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition."Biochem Biophys Res Com. 312. 1342-1348 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yokota T, et al.: "siRNA-based inhibition of superoxide dismutase expression ; potential use in familial Amyotrophic lateral sclerosis."Biochem Biophys Res Com. 314. 283-291 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Li Y, Yokota T, et al.: "siRNA-based Inhibition of Mutant atacin 3 : Sequence-dependent and independent discriminations of mutant and wild-type allekes by siRNA."Ann Neurol. 55. (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 横田隆徳: "変異遺伝子に選択的な遺伝子治療の戦略"神経内科. 56・1. 7-13 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 横田隆徳: "RNAiによる神経変性疾患の遺伝子治療をめざして"遺伝子医学. 7(3). 349-354 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 横田隆徳, 水澤英洋: "siRNAを用いたC型肝炎の遺伝子治療"Molecular Medicine. 41(1). 36-44 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 横田隆徳: "RNAiを用いたウイルス性肝炎の遺伝子治療"医学のあゆみ. 208(7). 485-491 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 横田隆徳: "神経変性疾患研究におけるRNAiを用いた遺伝子発現制御"バイオインダストリー. 21(4). 43-51 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 横田隆徳: "RNAiの医療への応用"実験医学. 22(4). 485-491 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 横田隆徳: "神経変性疾患へのRNAiの臨床応用の展望"最新医学. 59(4). 138-144 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] YOKOTA T, et al.: "siRNA-based inhibition specific for mutant SODI with single nucleotide alternation in familial ALS, compared with ribozyme and DNA enzyme"Biochemical and Biophysical Research Communication. 314. 283-291 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 横田隆徳: "RNAiによる神経変性疾患の遺伝子治療をめざして"遺伝子医学. 7・3. 349-354 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 横田隆徳: "RNAiの医療への応用"実験医学. 22・4. 485-491 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Li Y, et al.: "siRNA-based inhibition of Mutant ataxin3 gene expression : potential use for gene therapy of Machado-Joseph disease"Annals of Neurology. (印刷中).

    • Related Report
      2003 Annual Research Report
  • [Publications] Yokota T, et al.: "Inhibition of intracellular hepatitis C rims replication by synthetic and vector-drived small interfering RNAs"EMBO report. 4・6. 602-608 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ykota T, et al.: "Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome in inhibition"Biochemical and Biophysical Research Communication. 312. 1342-1348 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 横田隆徳: "変異遺伝子に選択的な遺伝子治療の戦略"神経内科. 56・1. 7-13 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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