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アデノ随伴ウイルス(AAV)ベクターの開発とその癌遺伝子治療への応用

Research Project

Project/Area Number 15025268
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionJichi Medical University

Principal Investigator

小澤 敬也 (小沢 敬也)  自治医科大学, 医学部, 教授 (30137707)

Co-Investigator(Kenkyū-buntansha) 水上 浩明 (水上 裕明)  自治医科大学, 医学部, 講師 (20311938)
卜部 匡司  自治医科大学, 医学部, 講師 (40213516)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥20,100,000 (Direct Cost: ¥20,100,000)
Fiscal Year 2004: ¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 2003: ¥10,100,000 (Direct Cost: ¥10,100,000)
Keywordsがん遺伝子治療 / AAVベクター / 組織特異性 / バキュロウイルス / 卵巣癌 / 可溶型Flt-1 / IL-10 / NK4
Research Abstract

アデノ随伴ウイルス(AAV : adeno-associated virus)ベクターは、安全性が高く、骨格筋などの非分裂細胞へ遺伝子導入可能で、そのような細胞では長期的な遺伝子発現が期待できる。そこで、抗腫瘍血管療法や癌の転移・播種の抑制を狙った治療法への応用が期待され、本研究では以下の研究を行った。1)AAVベクターの血清型と組織特異性に関する検討:AAV-1,2,5,7,8型AAVに由来するカプシドを持った各AAVベクター作製法を確立し、骨格筋に対しては1型及び7型由来のベクターが、また、門脈内投与においては8型由来のベクターが最大の効果を示した。各血清型のキャプシド蛋白質に対する免疫反応をELISA法で調べたところ、全てのマウスにおいてベクター投与後に抗体価の有意な上昇が確認できた。2)バキュロウイルスを利用したAAVベクター作製法の開発:AAVベクターの普及を阻んできたベクター作製技術の壁を打開するため、バキュロウイルスと昆虫細胞を利用したAAVベクター大量作製システムの開発を1,2,5型について行った。本法で作製したAAVベクターは、通常法によるものと機能的に差異がないことが判明した。3)AAVベクターを用いた癌に対する遺伝子治療ストラテジーの検討:応用研究では、卵巣癌の腹膜播種と癌性腹水の制御を目的に、可溶型Flt-1、IL-10の各遺伝子を搭載したAAVベクターを作製し、担癌ヌードマウスを用いて治療モデル実験を引き続き実施し、それぞれの治療用遺伝子の有効性を明らかにした。4)脂肪組織への遺伝子導入法:1型AAVベクターにプルロニック系界面活性剤を添加することで、脂肪組織への遺伝子導入効果を改善することができた。また、遺伝子導入を行った組織を完全に摘出することで、元の状態に戻すことができた。

Report

(2 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (23 results)

All 2005 2004 Other

All Journal Article (12 results) Publications (11 results)

  • [Journal Article] Repair of articular cartilage defect by autologous transplantation of basic fibroblast growth factor gene-transduced chondrocytes with adeno-associated virus vector.2005

    • Author(s)
      Yokoo, N.
    • Journal Title

      Arthritis Rheum. 52・1

      Pages: 164-170

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Adeno-associated virus vector-mediated interleukin-10 gene transferinhibits atherosclerosis in apolipoprotein E-deficient mice.2004

    • Author(s)
      Yoshioka, T.
    • Journal Title

      Gene Ther. 11・24

      Pages: 1772-1779

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Overexpression of a hybrid gene consisting of the amino-terminal fragment of urokinase and carboxyl-terminal domain of bikunin suppresses invasion and migration of human ovarian cancer cells in vitro2004

    • Author(s)
      Takei, Y.
    • Journal Title

      Int.J.Cancer. 113・1

      Pages: 54-58

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Topoisomerase inhibitors enhance the cytocidal effect of AAV-HSVtk/ganciclovir on head and neck cancer cells.2004

    • Author(s)
      Kanazawa, T
    • Journal Title

      Int.J.Oncol. 25・3

      Pages: 729-735

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Translocation and cleavage of myocardial dystrophin as a common pathway to advanced heart failure : a scheme for the progression of cardiac dysfunction.2004

    • Author(s)
      Toyo-Oka, T.
    • Journal Title

      Proc.Natl.Acad.Sci.U.S.A. 101・19

      Pages: 7381-7385

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors.2004

    • Author(s)
      Kuribara, R.
    • Journal Title

      Mol.Cell.Biol. 24・14

      Pages: 6172-6183

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The Adenovirus E1A and E1B19K genes provide a helper function for transfection-based AAV vector production.2004

    • Author(s)
      Matsushita, T., et al.
    • Journal Title

      J.Gen.Virol. 85・Pt8

      Pages: 2209-2214

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Successful gene transfer using adeno-associated virus vectors into the kidney : comparison among adeno-associated virus serotype 1 to 5 vectors in vitro and in vivo.2004

    • Author(s)
      Takeda, S.
    • Journal Title

      Nephron Exp.Nephrol. 96・4

      Pages: 119-126

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice.2004

    • Author(s)
      Mochizuki, S.
    • Journal Title

      Gene Ther. 11・13

      Pages: 1081-1086

    • Related Report
      2004 Annual Research Report
  • [Journal Article] In situ generation of pseudotyped retroviral progeny by adenovirus-mediated transduction of tumor cells enhances the killing effect of HSV-tk suicide gene therapy in vitro and in vivo.2004

    • Author(s)
      Okada T., et al.
    • Journal Title

      J.Gene Med. 6・3

      Pages: 288-299

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Separate control of Rep and Cap expression utilizing mutant and wild-type loxP sequences and improved packaging system for adeno-associated virus vector production.2004

    • Author(s)
      Mizukami, H.
    • Journal Title

      Mol.Biotechnol. 27・1

      Pages: 7-14

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Adeno-Associated Virus (AAV) vector-mediated liver- and muscle-directed transgene expression using various kinds of promoters and serotypes.2004

    • Author(s)
      Mochizuki, S.
    • Journal Title

      Gene Ther.Mol.Biol. 8・1

      Pages: 9-18

    • Related Report
      2004 Annual Research Report
  • [Publications] Mizukami, H.: "Separate control of Rep and Cap expression utilizing mutant and wild-type loxP sequences and improved packaging system for adeno-associated virus vector production."Mol.Biotechnol.. in press.

    • Related Report
      2003 Annual Research Report
  • [Publications] Mochizuki, S.: "Adeno-Associated Virus (AAV) vector-mediated liver- and muscle-directed transgene expression using various kinds of promoters and serotypes."Gene Ther and Mol Biol. in press.

    • Related Report
      2003 Annual Research Report
  • [Publications] Iwata, N.: "Presynaptic localization of neprilysin contributes to efficient clearance of amyloid-beta peptide in mouse brain."J.Neurosci. 24. 991-998 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ideno, J.: "Persistent phenotypic correction of central diabetes insipidus using adeno-associated virus vector-expressing arginine-vasopressin in brattleboro rats."Mol Ther. 8. 895-902 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kohno, T.: "Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer."Cancer Res.. 63. 5091-5094 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Urabe, M.: "Positive and negative effects of adeno-associated virus Rep on AAVS1-targeted integration."J.Gen.Virol.. 84. 2127-2132 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kanazawa, T.: "Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice."Gene Ther.. 10. 51-58 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Xin, K.Q.: "A DNA vaccine containing inverted terminal repeats from adeno-associated virus increases immunity to HIV."J.Gene.Med.. 5. 438-445 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kametaka, M: "Reduction of CTLL-2 cytotoxicity by induction of apoptosis with a Fas-estrogen receptor chimera"Cancer Sci.. 94. 639-643 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nomoto, T.: "Distinct patterns of gene transfer to gerbil hippocampus with recombinant adeno-associated virus type 2 and 5."Neurosci.Lett.. 340. 153-157 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamaguchi, T.: "Enhancement of thymidine kinase-mediated killing of malignant glioma by BimS, a BH3-only cell death activator."Gene Ther.. 10. 375-385 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2018-03-28  

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