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Molecular Pathogenesis of Brain Damage and Gene Therapy in Genetic Leukodystrophy

遗传性脑白质营养不良脑损伤的分子发病机制和基因治疗

基本信息

批准号：
11470176
负责人：
ETO Yoshikatsu
金额：
$ 9.54万
依托单位：
The Jikei University Shool of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470176/
关键词：
MLD gene therapy neural stem cell therapy Twitcher mice Sly mice 遺伝子異常 Sjogren-Larsson

项目摘要

1. Pathogenesis of Leukodystrophy in Globoide Cell Leukodystrophy and Other1) Using animal model of Krabbe globoid cell leukodystrophy(GLD), we tried to identified the cause of leukodytrophy in twitcher mice. The cause of neural cell damage might be caused by the influx of intracellular calcium in such mice which was demonstrated by patch cramp method. The increased intracellular calcium resulted in the activation of cellular protease and hense damage the neural cells.2) We studied the clinical phnotype and genotype in metachromatic leukodystrophy and also identified novel genotype in two cases with MLD. Furthermore, we demonstrated that the G99D mutation was neruological severe type and consisted of 50% of all genotype of Japanese MLD.3) Japanese patients with Sjogren Larrson syndrome shows particular genotype in Japanese.4) We studied the genotype identifications in Fabry disease which were L16H, A37V, W209X, 342QIVS-1-1 etc.2. Cell therapy and gene therapy in genetic leukodystrophyGene therapy and cell therapy were carried out using Twitcher mice and Sly Mice.1) Twitcher mice were treated with adenovirus vector which was administered into intraventricle, during fetal period. The number of globoid cells were decreased in treated animals after the administration of viral vetor. Simultaneously, the amount of psychosine was decreased in treated animals.2) Neural stem cells obtained fromhuman fetal brains were injected into Sly mice brain and the accumulated compounds in Sly mice were decreased. The data suggest that neural stem cells were effective for the treatment of The CNS involvement in these neurological mutants.3) Injection of mesenchymal stem cells into Sly mice showed decreased storage Materials and effective for neurological mice.

1. 球状细胞脑白质营养不良及其他脑白质营养不良的发病机制1）利用Krabbe球状细胞脑白质营养不良（GLD）动物模型，我们尝试鉴定twitcher小鼠脑白质营养不良的病因。膜片痉挛法证实该小鼠神经细胞损伤的原因可能是细胞内钙离子内流所致。细胞内钙的增加导致细胞蛋白酶的激活，从而损伤神经细胞。2)我们研究了异染性脑白质营养不良的临床表型和基因型，并在两例MLD病例中发现了新的基因型。此外，我们还证明G99D突变为神经系统严重型，占日本MLD所有基因型的50%。3）日本干燥综合征患者在日语中表现出特定的基因型。4）我们研究了法布里病的基因型鉴定，包括L16H、A37V、W209X、342QIVS-1-1等2。遗传性脑白质营养不良的细胞治疗和基因治疗采用Twitcher小鼠和Sly小鼠进行基因治疗和细胞治疗。1)用腺病毒载体治疗Twitcher小鼠，在胎儿期将腺病毒载体注射入脑室内。施用病毒载体后，治疗动物的球状细胞数量减少。同时，经治疗的动物中精神嘧啶的量也减少了。2)将从人胎儿大脑中获得的神经干细胞注射到Sly小鼠大脑中，Sly小鼠体内累积的化合物减少。数据表明，神经干细胞对于治疗这些神经突变体的中枢神经系统受累是有效的。3)将间充质干细胞注射到Sly小鼠体内显示储存材料减少，并且对神经小鼠有效。