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2003 Fiscal Year Final Research Report Summary

Development of prophylactic and therapeutic anti-prion drugs for the patients at high risks

Research Project

Project/Area Number 13557118
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Cerebral neurosurgery
Research InstitutionTohoku University (2003)
Kyushu University (2001-2002)

Principal Investigator

DOH-URA Katsumi  Tohoku University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (00263012)

Co-Investigator(Kenkyū-buntansha) IWAKI Toru  Tohoku University, Graduate School of Medical Sciences, Professor, 大学院・医学研究院, 教授 (40221098)
Project Period (FY) 2001 – 2003
Keywordsprion disease / prophylactic and therapeutic medicine / inhibition of prion biosynthesis / drug screening / persistently infected cell culture / animal experiment / pentsan polysulfate / intracerebroventricular administration
Research Abstract

In Japan, where iatrogenic Creutzfeldt-Jacob disease (CJD) or hereditary prion disease has occurred frequently, development of prophylaxis and therapeutics for prion diseases has been required. This research covered not only the basic research but also the clinical application of the therapeutic development, and the following points were clarified.
1.Many anti-prion compounds were discovered by screening with prion-infected cells. About 20 effective quinoline-ring vhemicals including several clinical medicines were found. More than 80 effective compaunds from benzothiazole-related chemicals or Congo red-related chemicals were discovered, and some of them were effective not only as therapeutic drugs but also as prion imaging probes capable of detecting abnormal prion protein deposition in the brain, when administered peripherally in the disease animal models. Pentosan polysulfate (SPS) and heparin derivatives were also found to he remarkably effective. Especially SPS was the most benefic … More ial, when administered intracerebroventricularly into the diseased animals.
On the one hand, interaction analyses between prion protein (PrP) and anti-prion chemicals revealed that most of the anti-prion chemicals exert their anti-prion activities by interacting directly with the PrP and thus inhibiting the abnormal conversion. Correlation between the interaction affinity and the anti-prion activity was demonstrated and thus wan possibly applied to high-throughput screening for anti-prion chemicals. Furthermore, it was shown that anti-prion activities of the anti-prion chemicals were dependent of infected cell types as well as pathogen strains.
2.About SPS which showed the most beneficial effects in the animal models, after checking the safety of its continuous intracerebroventricular infusion in experimental animals, experimental treatment was carried out in one British patient with variant CJD. In spite of his advanced clinical stage, intracerebroventricular SPS administration demonstrated more outstanding effects than expected, and it did not show any adverse effects. The findings in the patient, together with the findings in the animals model experiments, indicate that this treatment can be also used to prevent high-risk people from prion diseases. Less

  • Research Products

    (52 results)

All Other

All Publications (52 results)

  • [Publications] Kawashima T, et al.: "Apoptotic bodies in the cerebellum of Japanese patients with Creutzfeldt-Jacob disease."Pathology International. 51. 140-144 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Iida T, et al.: "An atypical case of sporadic Creutzfeldt-Jacob disease with Parkinson's disease."Neuropathology. 21. 294-297 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sasaki K, et al.: "Increased clusterin(apolipoprotein J) expression in human and mouse brains infected with transmissible spongiform encephalopathies."Acta Neuropathologica. 103. 199-208 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ando Y, et al.: "A novel tool for detecting amyloid deposits in systemic amyloidosis in vitro and in vivo."Laboratory Investigation. 83. 1751-1759 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sasaki K, et al.: "Neuropathological features of a case with schizophrenia and prion protein gene P102L mutation before onset of Gerstmann-Straussler-Scheinker disease."Acta Neuropathologica. 106. 92-96 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishida T, et al.: "Probable sporadic Creutzfeldt-Jakob disease with valine homozygosity at codon 129 and bilateral middle cerebellar peduncle lesions."Internal Medicine. 42. 199-202 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsuji Y, et al.: "Heidenhain variant of Creutzfeldt-Jakob disease diffusion weighted MRI and PET characteristics."Journal of Neuroimaging. 14. 63-66 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Jin K, et al.: "Clinical features of Creutzfeldt-Jakob disease with V180I mutation."Neurology. 62. 502-505 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Murakami-Kubo I, et al.: "Quinoline derivatives are therapeutic for transmissible spongiform encephalopathies."Journal of Virology. 78. 1281-1288 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Doh-ura K, et al.: "Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion."Journal of Virology. 78. 4999-5006 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Furukawa H, et al.: "A pitfall in diagnosis of human prion diseases using detection of protease-resistant prion protein in urine : contamination with bacterial outer membrane proteins."Journal of Biological Chemistry. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishikawa K, et al.: "Amyloid imaging probes are useful for evaluation and treatment of transmissible spongiform encephalopathies."Journal of General Virology. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Furukawa H, et al.: "Accumulation of prion protein in the muscle fibers of experimental chloroquine myopathy : in vivo model for deposition of prion protein in non neuronal tissues."Laboratory Investigation. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shiga Y, et al.: "Diffusion weighted MRI abnormalties as an early diagnostic marker for Creutzfeldt-Jakob disease."Neurology. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 高瀬敬一郎, 他: "高齢で発症したGerstmann-Straussler-Scheinker症候群の一例、プリオン蛋白遺伝子多型の検討"臨床神経学. 41. 318-321 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 佐竹真理恵, 他: "ヒト乾燥硬膜移植後に発症したと考えられたCreutzfeldt-Jakob病の1剖検例"大分県立病院医学雑誌. 30. 105-107 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 堂浦克美: "プリオン病、治療薬開発の現状と早期診断法開発の重要性"医学の歩み. 198. 403-406 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 堂浦克美: "プリオン病の分子病態と治療薬開発"最新医学. 56. 1644-1649 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 堂浦克美: "プリオン蛋白、プリオン病感染因子の本体?"CLINICAL NEUROSCIENCE. 19. 888-893 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 堂浦克美: "家族性プリオン病、発症遅延薬剤開発研究の現状"内科. 87. 649-655 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 堂浦克美: "ヒトのプリオン病とその治療薬剤開発の現状"ファルマシア. 38. 635-639 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 堂浦克美: "プリオン病の治療薬開発"医学のあゆみ. 203(10). 923-930 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 町田郁子, 他: "発症早期に脳病理所見を検討し得た散発性Creutzfeldt-Jakob病の1剖検例"神経内科. 56(6). 517-522 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 堂浦克美: "プリオン病.新興・再興感染症、輸入感染症の臨床と病理"病理と臨床. 21. 230-235 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 堂浦克美: "プリオン病治療薬の開発"神経研究の進歩. 47. 109-118 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 堂浦 克美: "脳科学研究の現状と課題 プリオン病研究の進歩(杉田秀夫、高橋清久 編集)"じほう社、東京. 324 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kawashima T, et al.: "Apoptotic bodies in the cerebellum of Japanese patients with Creutzfeldt-Jacob disease."Pathology International. 51. 140-144 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Iida T, et al.: "An atypical case of sporadic Creutzfeldt-Jocob disease with Parkinson's disease."Neuropathology. 21. 294-297 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sasaki K, et al.: "Increased clusterin (apolipoprotein J) expression in human and mouse brains infected with transmissible spongiform encephalopathies."Acta Neuropathologica. 103. 199-208 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ando Y, et al.: "A novel tool for detecting amyloid deposits in systemic amyloidosis in vitro and in vivo."Laboratory Investigation. 83. 1751-1759 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sasaki K, et al.: "Neuropathological features of a case with schizophrenia and prion protein gene P102L mutation before onset of Gerstmann-Straussler-Scheinker disease."Acta Neuropathologica. 106. 92-96 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishida T, et al.: "Probable sporadic Creutzfeldt-Jakob disease with valine homozygosity at codon 129 and bilateral middle cerebellar peduncle lesions"Internal Medicine. 42. 199-202 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsuji Y, et al.: "Heidenhain variant of Creutzfeldt-Jakob disease : diffusion-weighted MRI and PET characteristics."Journal of Neuroimaging. 14. 63-66 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Jin K, et al.: "Clinical features of Creutzfeldt-Jakob disease with VI80I mutation."Neurology. 62. 502-505 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Murakami-Kubo I, et al.: "Quinoline derivatives are therapeutic for transmissible spongiform encephalopathies."Journal of Virology. 78. 1281-1288 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Doh-ura K, et al.: "Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion."Journal of Virology. 78. 4999-5006 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Furukawa H, et al.: "A pitfall in diagnosis of human prion diseases using detection of protease-resistant prion protein in urine : contamination with bacterial outer membrane proteins"Journal of Biological Chemistry. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishikawa K, et al.: "Amyloid imaging probes are useful for evaluation and treatment of transmissible spongiform encephalopathies."Journal of General Virology. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Furukawa H, et al.: "Accumulation of prion protein in the muscle fibers of experimental chloroquine myopathy : in vivo model for deposition of prion protein in non-neuronal tissues."Laboratory Investigation. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shiga Y, et al.: "Diffusion-weighted MRI abnormalties as an early diagnostic marker for Creutzfeldt-Jakob disease."Neurology. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takase K, et al.: "A late disease onset case of Gerstmann-Straussler-Scheinker syndrome, evaluation of prion protein"Rinsho Shinkei. 41(JPN). 318-321 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Satake M, et al.: "An autopsy case of Creutfeldt-Jacob disease occurred after Cadaveric dura mater grafting."Acta Medica Ohita Prefectural Hospital. 30(JPN). 105-107 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Doh-ura K.: "Prion diseases, present status of the development of therapeutic drugs and importance of the development of clinical diagnostics."Igaku-no-ayumi. 198(Jpn). 403-406 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Doh-ura K.: "Molecular pathogenesis and development of therapeutics in prion diseases."Saishin Igaku. 56(Jpn). 1644-1649 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Doh-ura K.: "Prion protein is a pathogen of prion disease?"Clinical Neuroscience. 19(Jpn). 888-893 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Doh-ura K.: "Hereditary prion diseases and present status of prophylactic drug development."Naika. 87(Jpn). 649-655 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Doh-ura K.: "Human prion diseases and therapeutic drug development."Pharmacia. 38(Jpn). 635-639 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Doh-ura K.: "Development of anti-prion disease drugs."Igaku-no-ayumi. 203(10)(Jpn). 923-930 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Machida I, et al.: "A case of sporadic Creutzfeldt-Jakob disease diagnosed by autopsy at an early disease stage."Shinkei Naika. 56(6)(Jpn). 517-522 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Doh-ura K.: "Prion diseases, clinical and pathological features."Byori-to-rinsho. 21(Jpn). 230-235 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Doh-ura K.: "Development of anti-prion disease drugs."Shinkeikenkyu-no-shinpo. 47(Jpn). 109-118 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Doh-ura K.: "Advances in prion disease research."the topics and challenge of neuroscience research. (Eds. by Sugita H and Takahashi K)(Jiho, Tokyo). 324. (2003)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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