Gene therapy for inherited neurodegenerative disease using fetal bone marrows stem cell transplantation.

使用胎儿骨髓干细胞移植治疗遗传性神经退行性疾病的基因疗法。

基本信息

  • 批准号:
    05670701
  • 负责人:
  • 金额:
    $ 1.22万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)
  • 财政年份:
    1993
  • 资助国家:
    日本
  • 起止时间:
    1993 至 1994
  • 项目状态:
    已结题

项目摘要

In this experiment, we tried to elucidate the mechanism of pathogenesis of humann Niemann-Pick disease type C and to have a basic approach for cloning of the defective gene in NPC and to create gene therapy for rat fetus by using of retrovirus vector.1) We detected the attenuated elevation of cytoplasmic calcium concentration following the uptaking of Low Density Lipoprotein in type C Niemann-Pick fibroblast. Moreover, we found that calcium channel agonist (YC-170) improve the attemuated elevation of calcium concentration and the deficient cholesterol esterification by 40% and 90% of normal control, respectively. These data indicate that the attemuated elevation of cytoplasmic calcim concentration was strongly related to the etiology of humann Niemann-Pick disease type C.2) We confirmed the synthesis of cholesterol within cells was strongly accelerated in transformed NPC fibroblast by origin defective simian virus 40 and we showed the hypersensitivity of NPC cell lines transformed by SV40 to HMG-CoA reductase inhibitor (Lovastatin, Sinvastatin). Therefor, these cell lines and HMG-CoA reductase inhibitor could be useful for the cloning of the defective gene in NPC.3) We have the succesful transduction and expression of ASA gene in human MLD fibroblast using a newly developed retroviral vector. This is a first step in evaluating the potential of gene therapy for congenital metabolic disorder. And we tried to have the gene theraly for rat fetus by using this developed retroviral vector transduced with ASA gene. After injection of this vector into amonion vein, we tried to find the expression of ASA gene in several organs such as liver, spleen, and kidny but we could not find any protein expression in these organs by immunohistochemical staining of human ASA antibody. Now we are trying to have gene therapy of MPS mouse fetus by using adeno associated vector which was transduced by alpha-glucuronidase gene.
本实验旨在阐明人类尼曼-匹克病C型的发病机制,为NPC缺陷基因的克隆及利用逆转录病毒载体构建大鼠胎儿基因治疗提供基本途径。1)我们检测到C型Niemann-Pick成纤维细胞摄取低密度脂蛋白后细胞质钙浓度升高的减弱。此外,我们发现钙通道激动剂(YC-170)对钙浓度升高的减弱和胆固醇酯化缺陷的改善分别比正常对照组提高了40%和90%。这些数据表明,细胞质钙浓度升高的减弱与人类尼曼-匹克病c型的病因密切相关。2)我们证实了来源缺陷猿病毒40转化的鼻咽癌成纤维细胞中细胞内胆固醇的合成被强烈加速,我们发现SV40转化的鼻咽癌细胞系对HMG-CoA还原酶抑制剂(洛伐他汀,辛伐他汀)过敏。因此,这些细胞系和HMG-CoA还原酶抑制剂可用于npc缺陷基因的克隆。3)我们利用新开发的逆转录病毒载体成功转导并表达了ASA基因在人MLD成纤维细胞中的表达。这是评估基因治疗先天性代谢紊乱潜力的第一步。我们尝试用这种开发的带有ASA基因转导的逆转录病毒载体对大鼠胎儿进行基因治疗。将该载体注入洋葱静脉后,我们试图在肝、脾、肾等器官中寻找ASA基因的表达,但通过人ASA抗体的免疫组化染色未发现这些器官中有任何蛋白表达。目前,我们正尝试利用α -葡萄糖醛酸酶基因转导的腺相关载体对MPS小鼠胎儿进行基因治疗。

项目成果

期刊论文数量(21)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Yamoto T., Tokoro T., el al.: "The attenuated elevation of cytoplasmic calicium concentration following the up take of low density lipoprotein in type C Niemann-Pick disease." Biochem.Biophys.Res.Commun.198. 438-444 (1994)
Yamoto T.、Tokoro T. 等人:“C 型尼曼-皮克病中摄取低密度脂蛋白后细胞质钙浓度的升高减弱。”
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    0
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Tokoro T.,et al.: "Therapeutic NMDA antagonist trial nonketotic hyperglycinemia in an infant." Jikeikai Med.J.41. 155-161 (1994)
Tokoro T.,et al.:“治疗性 NMDA 拮抗剂试验婴儿非酮症高甘氨酸血症。”
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    0
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Tokoro T., et al.: "Therapeutic NMDA antagonist trial nonketotic Hyperglycinemia in an infant." Jikeikai Medical J.41. 155-161 (1994)
Tokoro T. 等人:“婴儿中的治疗性 NMDA 拮抗剂试验非酮症高血糖症。”
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    0
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Yamamoto T.,Tokoro T.,at el.: "Type C Nimenn-Pick disease fibroblasts and their transformed cell lines are hypersensitive to---" J.Inher.Metab.Dis.17. 718-723 (1994)
Yamamoto T.,Tokoro T.,等人:“C 型 Nimenn-Pick 病成纤维细胞及其转化细胞系对——”J.Inher.Metab.Dis.17 过敏。
  • DOI:
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    0
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  • 通讯作者:
Tokoro T., et al.: "Therapeutic NMDA antagonist trial nonketotic hyperglycinemia in an infant." Jikei.Med.J.41. 155-161 (1994)
Tokoro T. 等人:“婴儿中的治疗性 NMDA 拮抗剂试验非酮症高甘氨酸血症。”
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TOKORO Toshiharu其他文献

TOKORO Toshiharu的其他文献

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{{ truncateString('TOKORO Toshiharu', 18)}}的其他基金

Treatment for congenital metabolic disorder with brain dysfunction.
治疗伴有脑功能障碍的先天性代谢紊乱。
  • 批准号:
    11670791
  • 财政年份:
    1999
  • 资助金额:
    $ 1.22万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Pathogenesis of Demyelination in Krabbe's disease and it's therapy
克拉伯病脱髓鞘的发病机制及治疗
  • 批准号:
    63570456
  • 财政年份:
    1988
  • 资助金额:
    $ 1.22万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)
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