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The development of molecular therapy using decoy oligonucleotides : for clinical applications.

Research Project

Project/Area Number 15590744
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionOsaka University

Principal Investigator

AOKI Motokuni  Osaka University, Graduate School of Medicine, assistant processor, 医学系研究科, 助手 (00346214)

Co-Investigator(Kenkyū-buntansha) MORISHITA Ryuichi  Osaka University, Graduate School of Medicine, professor, 医学系研究科, 寄附講座教授 (40291439)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥2,600,000 (Direct Cost: ¥2,600,000)
KeywordsMolecular therapy / Decoy oligonucleotides / NFkB / ets / Aneurysm / Graft failure / Restenosis / Atherosclerosis / キメラデコイ / 大動脈瘤 / MMP / J-PRAN
Research Abstract

In this program, we developed a newly system, chimeric decoy strategy which regulate the activity of two transcription factors, and evaluated the possibility of novel molecular therapies for cardiovascular diseases based on atherosclerosis.
1) Abdominal aortic aneurysm (AAA) is a common degenerative condition associated with aging and atherosclerosis. To develop a novel therapeutic approach, we examined the simultaneous inhibition of the transcription factors NFkB and ets, which regulate inflammation and matrix degradation, in a rabbit AAA model. Ultrasound and angiographic analysis demonstrated that treatment with chimeric decoy oligodeoxynucleotides significantly prevented the progression of elastase-induced aortic dilatation. Transfection of chimeric decoy oligodeoxynucleotides reduced the activities of MMP-2 and MMP-9 as compared to scrambled decoy oligodeoxynucleotides. Treatment with chimeric decoy oligodeoxynucleotides markedly inhibited the proteolysis of elastin as compared to … More scrambled decoy oligodeoxynucleotides. Interestingly, immunohistochemical study demonstrated that macrophage infiltration of mainly the adventitia and media was significantly inhibited by transfection of chimeric decoy oligodeoxynucleotides.
2) Although autologous vein remains the commonly used conduit for bypass grafts, neointimal hyperplasia is known to be one of the major disease processes in vein graft failure. We investigated the inhibitory effect of NFkB decoy oligodeoxynucleotides (ODN) on prevention of vein graft failure in a rabbit hypercholesterolemic model. Four weeks after vein implantation, the treatment with NFkB decoy ODN significantly suppressed intimal hyperplasia. Treatment of NFkB decoy ODN significantly inhibited the recruitment of macrophages and the proliferation of vascular smooth muscle cells (VSMC), while the apoptosis in VSMC was significantly increased by NFkB decoy ODN. Moreover, transfection of chimeric decoy ODN against E2F and NFkB resulted in significantly inhibition of anastomotic intimal hyperplasia. Immunohistochemical staining revealed that chimera decoy ODN inhibited DNA synthesis and the migration of macrophages, followed by the inhibition of inflammatory changes. These findings raised the possibility of novel strategy for prevention of graft failure. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (55 results)

All 2004 2003 Other

All Journal Article (47 results) Book (7 results) Publications (1 results)

  • [Journal Article] Local delivery of E2F decoy oligodeoxynucleotides using ultrasound with microbubble agent (Optison) inhibits intimal hyperplasia after balloon injury in rat carotid artery model.2004

    • Author(s)
      Hashiya N
    • Journal Title

      Biochemical Biophysical Research Communications 317

      Pages: 508-514

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of experimental abdominal aortic aneurysm in the rat by use of decoy oligodeoxynucleotides suppressing activity of NFkB and ets transcription factors.2004

    • Author(s)
      Nakashima H
    • Journal Title

      Circulation 109

      Pages: 132-138

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] No influence of tumor growth by intramuscular injection of hepatocyte growth factor plasmid DNA : safety evaluation of therapeutic angiogenesis gene therapy in mice.2004

    • Author(s)
      Matsuki A
    • Journal Title

      Biochemical Biophysical Research Communications 315

      Pages: 59-65

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] In vivo evidence of angiogenesis induced by transcription factor, ets-1:ets-1 is located upstream of angiogenesis cascade.2004

    • Author(s)
      Hashiya N
    • Journal Title

      Circulation 109

      Pages: 3035-3041

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease by therapeutic angiogenesis.2004

    • Author(s)
      Morishita R
    • Journal Title

      Hypertension 44

      Pages: 203-209

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Effect of nifedipine on endothelial function in normotensive smokers : potential contribution of increase in circulating hepatocyte growth factor.2004

    • Author(s)
      Yamasaki K
    • Journal Title

      Journal of Human Hypertension 18(10)

      Pages: 701-705

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Development of efficient plasmid DNA transfer into adult rat central nervous system using microbubble-enhanced ultrasound.2004

    • Author(s)
      Shimamura M
    • Journal Title

      Gene Therapy Gene Ther 11(20)

      Pages: 1532-1539

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of neointimal hyperplasia after balloon injury by cis-element ‘decoy' of early growth response gene-1 in hypercholesterolemic rabbits.2004

    • Author(s)
      Ohtani K
    • Journal Title

      Gene Ther 11(2)

      Pages: 126-132

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transcription factor decoy for AP-1 reduces mesangial cell proliferation and extracellular matrix production in vitro and in vivo.2004

    • Author(s)
      Ahn JD
    • Journal Title

      Gene Ther 11(11)

      Pages: 916-923

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gene therapy with an E2F transcription factor decoy inhibits cell cycle progression in rat anti-Thy 1 glomerulonephritis.2004

    • Author(s)
      Tomita N
    • Journal Title

      Int J Mol Med 13(5)

      Pages: 629-636

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Local delivery of E2F decoy oligodeoxynucleotides using ultrasound with microbubble agent (Optison) inhibits intimal hyperplasia after balloon injury in rat carotid artery model.2004

    • Author(s)
      Hashiya N.
    • Journal Title

      Biochemical Biophysics Research Communications 317

      Pages: 508-514

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of experimental abdominal aortic aneurysm in the rat by use of decoy oligodeoxynucleotides suppressing activity of NFkB and ets transcription factors.2004

    • Author(s)
      Nakashima H.
    • Journal Title

      Circulation 109

      Pages: 132-138

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] No influence of tumor growth by intramuscular injection of hepatocyte growth factor plasmid DNA : safety evaluation of therapeutic angiogenesis gene therapy in mice.2004

    • Author(s)
      Matsuki A.
    • Journal Title

      Biochemical Biophysics Research Communications 315

      Pages: 59-65

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] In vivo evidence of angiogenesis induced by transcription factor, ets-1 : ets-1 is located upstream of angiogenesis cascade.2004

    • Author(s)
      Hashiya N.
    • Journal Title

      Circulation 109

      Pages: 3035-3041

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease by therapeutic angiogenesis.2004

    • Author(s)
      Morishita R.
    • Journal Title

      Hypertension 44

      Pages: 203-209

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Effect of nifedipine on endothelial function in normotensive smokers : potential contribution of increase in circulating hepatocyte growth factor.2004

    • Author(s)
      Yamasaki K.
    • Journal Title

      Journal of Human Hypertension 18(10)

      Pages: 701-705

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Development of efficient plasmid DNA transfer into adult rat central nervous system using microbubble-enhanced ultrasound.2004

    • Author(s)
      Shimamura M.
    • Journal Title

      Gene Therapy Gene Ther 11(20)

      Pages: 1532-1539

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of neointimal hyperplasia after balloon injury by cis-element 'decoy' of early growth response gene-1 in hypercholesterolemic rabbits.2004

    • Author(s)
      Ohtani K.
    • Journal Title

      Gene Ther 11(2)

      Pages: 126-132

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transcription factor decoy for AP-1 reduces mesangial cell proliferation and extracellular matrix production in vitro and in vivo.2004

    • Author(s)
      Ahn JD.
    • Journal Title

      Gene Ther 11(11)

      Pages: 916-923

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gene therapy with an E2F transcription factor factor decoy inhibits cell cycle progression in rat anti Thy-1 glomerulonephritis.2004

    • Author(s)
      Tomita N.
    • Journal Title

      Int J Mol Med 13(5)

      Pages: 629-636

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Application of decoy oligodeoxynucleotides-based approach to renal diseases.2004

    • Author(s)
      Tomita N.
    • Journal Title

      Curr Drug Targets 5(8)

      Pages: 717-733

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Molecular therapy to inhibit NFkappaB activation by transcription factor decoy oligonucleotides.2004

    • Author(s)
      Morishita R.
    • Journal Title

      Curr Opin Pharmacol 4(2)

      Pages: 139-146

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gene Therapy vs Pharmacotherapy.2004

    • Author(s)
      Morishita R.
    • Journal Title

      Cardiovascular Genomics

      Pages: 137-156

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] HVJ-envelope vector for gene transfer into central nervous system.2003

    • Author(s)
      Shimamura M
    • Journal Title

      Biochemical Biophysics Research Communications 300

      Pages: 464-471

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of NFkB activation using cis-element "decoy" of NFkB binding site reduces neointimal formation in porcine balloon-injured coronary artery model.2003

    • Author(s)
      Yamasaki K
    • Journal Title

      Gene Therapy 10

      Pages: 356-364

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Enhanced angiogenesis and improvement of neuropathy by co-transfection of human hepatocyte growth factor and prostacyclin synthase gene.2003

    • Author(s)
      Koike H
    • Journal Title

      The FASEB Journal 17

      Pages: 779-781

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Improvement of endothelial dysfunction by angiotensin II blockade, accompanied by induction of vascular hepatocyte growth factor system in diabetic spontaneously hypertensive rats.2003

    • Author(s)
      Matsumoto K
    • Journal Title

      Heart & Vessels 18

      Pages: 18-25

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Angiogenic property of hepatocyte growth factor is dependent on up-regulation of essential transcription factor for angiogenesis, ets-1.2003

    • Author(s)
      Tomita N
    • Journal Title

      Circulation 107

      Pages: 1411-1417

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Angiogenesis induced by endothelial nitric oxide synthase gene through VEGF expression in rat hindlimb ischemia model.2003

    • Author(s)
      Namba T
    • Journal Title

      Circulation 108

      Pages: 2250-2257

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Increase in peripheral blood flow by intravenous administration of prostaglandin E1 in patients with peripheral arterial disease, accompanied by up-regulation of hepatocyte growth factor (HGF).2003

    • Author(s)
      Makino H
    • Journal Title

      Hypertension Research 27

      Pages: 85-91

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transfection of NFkappaB-decoy oligodeoxynucleotides using efficient ultrasound-mediated gene transfer into donor kidneys prolonged survival of rat renal allografts.2003

    • Author(s)
      Azuma H
    • Journal Title

      Gene Ther 10(5)

      Pages: 415-425

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nuclear factor kappa B decoy oligodeoxynucleotides prevent endotoxin-induced fatal liver failure in a murine model.2003

    • Author(s)
      Ogushi I
    • Journal Title

      Hepatology 38(2)

      Pages: 335-344

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] HVJ-envelope vector for gene transfer into central nervous system.2003

    • Author(s)
      Shimamura M.
    • Journal Title

      Biochemical Biophysics Research Communications 300

      Pages: 464-471

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of NFkB activation using cis-element "decoy" of NFkB binding site reduces neointimal formation in porcine balloon-injured coronary artery model.2003

    • Author(s)
      Yamasaki K.
    • Journal Title

      Gene Therapy 10

      Pages: 356-364

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Enhanced angiogenesis and improvement of neuropathy by co-transfection of human hepatocyte growth factor and prostacyclin synthase gene.2003

    • Author(s)
      Koike H.
    • Journal Title

      The FASEB Journal 17

      Pages: 779-781

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Improvement of endothelial dysfunction by angiotensin II blockade, accompanied by induction of vascular hepatocyte growth factor system in diabetic spontaneously hypertensive rats.2003

    • Author(s)
      Matsumoto K.
    • Journal Title

      Heart & Vessels 18

      Pages: 18-25

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Angiogenic property of hepatocyte growth factor is dependent on up-regulation of essential transcription factor for angiogenesis, ets-1.2003

    • Author(s)
      Tomita N.
    • Journal Title

      Circulation 107

      Pages: 1411-1417

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Angiogenesis induced by endothelial nitric oxide synthase gene through VEGF expression in rat hindlimb ischemia model.2003

    • Author(s)
      Namba T.
    • Journal Title

      Circulation 108

      Pages: 2250-2257

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Increase in peripheral blood flow by intravenous administration of prostaglandin E1 in patients with peripheral arterial disease, accompanied by up-regulation of hepatocyte growth factor (HGF).2003

    • Author(s)
      Makino H.
    • Journal Title

      Hypertension Research 27

      Pages: 85-91

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transfection of NFkappaB-decoy oligodeoxynucleotides using efficient ultrasound-mediated gene transfer into donor kidneys prolonged survival of rat renal allografts.2003

    • Author(s)
      Azuma H.
    • Journal Title

      Gene Ther 10(5)

      Pages: 415-425

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nuclear factor kappa B decoy oligodeoxynucleotides prevent endotoxin-induced fatal liver failure in a murine model.2003

    • Author(s)
      Ogushi I.
    • Journal Title

      Hepatology 38(2)

      Pages: 335-344

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Development of novel decoy oligonucleotides : advantages of circular dumbbell decoy.2003

    • Author(s)
      Tomita N.
    • Journal Title

      Curr Opin Mol Ther 5(2)

      Pages: 107-112

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Therapeutic potential of oligonucleotide-Based therapy in cardiovascular disease.2003

    • Author(s)
      Morishita R.
    • Journal Title

      Biodrugs 17(6)

      Pages: 383-389

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gene therapy with transcription factor decoy oligonucleotides as a potential treatment for cardiovascular diseases.2003

    • Author(s)
      Tomita N.
    • Journal Title

      Curr Drug Targets 4(4)

      Pages: 339-346

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transcription factors as molecular targets : molecular mechanisms of decoy ODN and their design.2003

    • Author(s)
      Tomita N.
    • Journal Title

      Curr Drug Targets 4(8)

      Pages: 603-608

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of ets, an essential transcription factor for angiogenesis, to prevent the development of abdominal aortic aneurysm in a rat model.

    • Author(s)
      Miwa K
    • Journal Title

      Gene Ther (投稿中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of ets, an essential transcription factor for angiogenesis, to prevent the development of abdominal aortic aneurysm in a rat model.

    • Author(s)
      Miwa K.
    • Journal Title

      Gene Ther (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Application of decoy oligodeoxynucleotides-based approach to renal diseases.2004

    • Author(s)
      Tomita N
    • Publisher
      Curr Drug Targets
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Cuff Opin Pharmacol Molecular therapy to inhibit NFkappaB activation by transcription factor decoy oligonucleotides.2004

    • Author(s)
      Morishita R
    • Publisher
      Curr Opin Pharmacol
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Gene Therapy vs Pharmacotherapy.2004

    • Author(s)
      Morishita R
    • Publisher
      Cardiovascular Genomics
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Development of novel decoy oligonucleotides : advantages of circular dumb-bell decoy.2003

    • Author(s)
      Tomita N
    • Publisher
      Cuff Opin Mol Ther
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Therapeutic potential of oligonucleotide-based therapy in cardiovascular disease.2003

    • Author(s)
      Morishita R
    • Publisher
      Biodrugs
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Gene therapy with transcription factor decoy oligonucleotides as a potential treatment for cardiovascular diseases.2003

    • Author(s)
      Tomita N
    • Publisher
      Curr Drug Targets
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Transcription factors as molecular targets : molecular mechanisms of decoy ODN and their design.2003

    • Author(s)
      Tomita N
    • Publisher
      Curr Drug Targets
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Nakashima H, Aoki M et al.: "Inhibition of experimental abdominal aortic aneurysm in the rat by use of decoy oligodeoxynucleotides....."Circulation. 109(1). 132-138 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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