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Preclinical tests for gene therapy of advanced heart failure

Research Project

Project/Area Number 14207033
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionThe University of Tokyo

Principal Investigator

TOYO-OKA Teruhiko  The University of Tokyo, Health Service Center, Professor, 保健センター, 教授 (00146151)

Co-Investigator(Kenkyū-buntansha) KURACHI Kotoku  National Institute of Advanced Industrial Science and Technology, Age Dimension Research Center, Dean, 年齢軸生命工学研究センター, センター長(研究職) (70344223)
OZAWA Keiya  Jichi Medical School, Division of Gene Therapy, Professor, 遺伝子治療部, 教授 (30137707)
TOBKUNAGA Katsushi  The University of Tokyo, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (40163977)
UEHARA Yoshio  The University of Tokyo, Health Service Center, Associate Professor, 保健センター, 助教授 (40184965)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥50,050,000 (Direct Cost: ¥38,500,000、Indirect Cost: ¥11,550,000)
Fiscal Year 2004: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
Fiscal Year 2003: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000)
Fiscal Year 2002: ¥24,960,000 (Direct Cost: ¥19,200,000、Indirect Cost: ¥5,760,000)
KeywordsCardiac failure / Gene therapy / Pre-clinical studies / 細胞膜の透過性 / ジストロフィン / 拡張型心筋症 / サルゴグリカン / 細胞移植 / rAAVベクター
Research Abstract

Considerable results was obtained in the first 3 objects, i.e. (1)Preparation of advanced heart failure of human-mimicking type in large animals, (2)Verification of safety and efficacy of gene therapy and (3)Development of reconstructed cell-based therapy. We have identified responsible gene for congenital dilated cardiomyopathy (DCM) as a mutation of δ-sarcoglycan gene (Sakamoto et al., PNAS,1997). Then, we have for the first time succeeded in gene therapy with using stable and long-lasting rAAV vector (Kawada et al, PNAS,2002). Different from other vectors, rAAV was safe and biologically inert. To extend our project for clinical study using apes, we had to consume one and a half year for the permission of the Ministry of Education, Culture, Science and Technology. Our final paradigm that heart failure is proceeded by a common mechanism secondary to dystrophin disruption and increment of sarcolemmal permeability, irrespective of hereditary or acquired origins and acute or chronic processes was common to heart failure in general including human DCM was extremely precious, because these data were not ethically obtained without employing apes (Toyo-oka et al., PNAS,2004). These results would provide a promising fruit to develop for the clinical application, and we do ask future fund.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (34 results)

All 2005 2004 Other

All Journal Article (18 results) Book (2 results) Publications (14 results)

  • [Journal Article] Effects of ACE inhibitor and AT(1) blocker on dystrophin-related proteins and calpain in failing heart.2005

    • Author(s)
      Takahashi M. et al.
    • Journal Title

      Cardiovasc.Res. 65

      Pages: 356-365

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A novel paradigm for the development of advanced heart failure-Assessment by gene therapy (A review).2005

    • Author(s)
      Kawada T. et al.
    • Journal Title

      Pharmacol.& Therap. (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A novel scheme of dystrophin disruption for the progression of advanced heart failure (A review).2005

    • Author(s)
      Kawada T. et al.
    • Journal Title

      Biochim.Biophys.Acta (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Effects of ACE inhibitor and AT(1) blocker on dystrophin-related proteins and calpain in failing heart.2005

    • Author(s)
      Takahashi M, Tanonaka K, Yoshida H, Oikawa R, Koshimizu M, Daicho T, Toyo-oka T, Takeo S.
    • Journal Title

      Cardiovasc.Res. 65

      Pages: 356-365

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A novel paradigm for the development of advanced heart failure-Assessment by gene therapy-.2005

    • Author(s)
      Kawada T, Masui F, Kumagai H, Koshimizu M, Nakazawa M, Toyo-oka T.
    • Journal Title

      Pharmacol. & Therap. (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A novel scheme of dystrophin disruption for the progression of advanced heart failure.2005

    • Author(s)
      Kawada T, Tezuka A, Ebisawa T, Masui F, Kumagai H, Nakazawa M, Toyo-oka T.
    • Journal Title

      Biochim.Biophys.Acta (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Effects of ACE inhibitor and AT(1) blocker on dystrophin-related proteins and calpain in failing heart.2005

    • Author(s)
      Takahashi M, Tanonaka K, Yoshida H, et al.
    • Journal Title

      Cardiovasc.Res. 65

      Pages: 356-365

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A novel paradigm for the development of advanced heart failure-Assessment by gene therapy (A review).2005

    • Author(s)
      Kawada T, Masui F, Kumagai H, et al.
    • Journal Title

      Pharmacol.&Therap. (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A novel scheme of dystrophin disruption for the progression of advanced heart failure(A review).2005

    • Author(s)
      Kawada T, Tezuka A, Ebisawa T, et al.
    • Journal Title

      Biochim.Biophys.Acta (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Translocation and cleavage of myocardial dystrophin as a common pathway to advanced heart failure.2004

    • Author(s)
      Toyo-oka T. et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA. 101

      Pages: 7381-7385

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] RNAi induction and activation in mammalian muscle cells where Dicer and eIF2C translation initiation factors are barely expressed.2004

    • Author(s)
      Sago N.et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 319

      Pages: 50-57

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Ursodeoxycholic acid inhibits endothelin-1 production in human vascular endothelial cells.2004

    • Author(s)
      Ma J.et al.
    • Journal Title

      Eur.J.Pharmacol. 505

      Pages: 67-74

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [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, Kawada T, Nakata J, et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA. 101

      Pages: 7381-7385

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] RNAi induction and activation in mammalian muscle cells where Dicer and eIF2C translation initiation factors are barely expressed.2004

    • Author(s)
      Sago N, Omi K, Tamura Y, Kunugi H, et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 319

      Pages: 50-57

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure : the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial.2004

    • Author(s)
      Hori M, Sasayama S, Kitabatake A, et al.
    • Journal Title

      Am.Heart.J. 147

      Pages: 324-330

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Ursodeoxycholic acid inhibits endothelin-1 production in human vascular endothelial cells.2004

    • Author(s)
      Ma J, Iida H, Jo T, Takano H, Oonuma H, Morita T, Toyo-oka T, Omata M, Nagai R, Okuda Y, Yamada N, Nakajima T.
    • Journal Title

      Eur.J.Pharmacol. 505

      Pages: 67-74

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Translocation and cleavage of myocardial dystrophin as a common pathway to advanced heart failure.2004

    • Author(s)
      Toyo-oka T, Kawada T, Nakata J et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA. 101

      Pages: 7381-7385

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Ursodeoxycholic acid inhibits endothelin-1 production in human vascular endothelial cells.2004

    • Author(s)
      Ma J, Iida H, Jo T, et al.
    • Journal Title

      Eur.J.Pharmacol. 505

      Pages: 67-74

    • Related Report
      2004 Annual Research Report
  • [Book] Troponin Revisited : Biochemistry, Molecular Biology and Pathophysiology(Tanokura, M, Ohtsuki I, and Maruyama K.)2005

    • Author(s)
      Toyo-oka T.
    • Total Pages
      300
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Troponin Revisited : Biochemistry, Molecular Biology and Pathophysiology2005

    • Author(s)
      Toyo-oka T., Kumagai H.
    • Total Pages
      300
    • Publisher
      Tanokura, M, Ohtsuki I, Maruyama K.
    • Related Report
      2004 Annual Research Report
  • [Publications] Hakamada-Taguchi R, Uehara Y, et al.: "Inhibition of hydroxymethylglutaryl-coenzyme a reductase reduces Th1 development and promotes Th2 development."Circ.Res.. 93:2003. 948-956 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Koizumi T, Hikiji H, Takato T, et al.: "Cell density and growth-dependent down-regulation of both intracellular calcium responses to agonist stimuli and expression of smooth-surfaced endoplasmic reticulum in MC_3T_3-E_1 osteoblast-like cells."J.Biol.Chem.. 278. 6433-6439 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Numabe A, Ara N, Hakamada Taguchi R, et al.: "Effects of the anti-platelet aggregation drug dilazep on cognitive function in Dahl salt-sensitive rats."Hypertens.Res.. 26. 185-191 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Abe T, Hikiji H, Takato T, et al.: "Targeting of iNOS with antisense DNA plasmid prevents cytokine-induced reduction of osteoblastic activity."Am.J.Physiol.. 285. E614-E621 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida H, Takahashi M, Koshimizu M, et al.: "Decrease in sarcoglycans and dystrophin in failing heart following acute myocardial infarction."Cardiovasc Res.. 59. 419-427 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hori K, Shin WS, Hemmi C, et al.: "High fidelity SNP genotyping using sequence-specific primer elongation and fluorescence correlation spectroscopy."Curr Pharm Biotechnol.. 4. 477-484 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Toyo-oka, Kawada T: "Signal transduction and cardiac hypertrophy"Kluwer Acad Publ.(Boston, Dordrecht, London). 449-459 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kawada T, Nakazawa M, Nakauchi S, et al.: "Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy"Proc.Natl.Acad.Sci.USA. 99(2). 901-906 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Terasawa K, Nakajima T, Iida H, Iwasawa K, et al.: "Nonselective cation currents regulate membrane potential of rabbit coronary arterial cell : modulation by lysophosphatidylcholine"Circulation. 106(24). 3111-3119 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Toyo-oka T, Kawada T, Xi H, Nakazawa M. et al.: "Gene therapy prevents disruption of dystrophin-related proteins in a model of hereditary dilated cardiomyopathy in hamsters"Heart, Lung & Circulation. 11(12). 174-181 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hakamada-Taguchi R, Uehara Y, Haebara T, Negoro H, Toyo-oka T: "The relationship between changes in normal-range systolic blood pressure and cognitive function in middle-aged healthy women"Hypertens Res.. 25(4). 565-569 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Negoro H, Shin SW, Hakamada-Taguchi R, et al.: "Endogenous prostaglandin D2 synthesis reduces an increase in plasminogen activator inhibitor-1 following interleukin stimulation in bovine endothelial cells"J.Hypertens.. 20(7). 1347-1354 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsuji T, Suzuki J, Shimamoto R, et al.: "Vector analysis of the wall shear rate at the human aortoiliac bifurcation using cine MR velocity mapping"Am J Roentgenol. 178(4). 995-999 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shin WS, Hemmi C, Toyo-oka T: "Methods in Molecular Biology"Co-culture and crosstalk between endothelial cells and vascular smooth muscle cells mediated by intracellular calcium. Med.Res.Council. 347-357 (2002)

    • Related Report
      2002 Annual Research Report

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

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