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Basic study on gene therapy for subacute sclerosing panencephalitis

亚急性硬化性全脑炎基因治疗基础研究

基本信息

批准号：
11670779
负责人：
MATSUOKA Osamu
金额：
$ 1.92万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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/grant/KAKENHI-PROJECT-11670779/
关键词：
Subacute sclerosing panencephalitis SSPE virus Gene therapy

项目摘要

Subacute sclerosing panencephalitis (SSPE) is a progressive and degenerative disease of the central nervous system of children and adolescents. It is caused by slow virus infection of measles virus which invaded at acute measles. SSPE is rare but lethal ; no curable treatment has not yet been established. We planed to kill SSPE virus-infected cells selectively transfected with plasmid containing E. coli-derived cytosine deaminase (CD) gene by treating with 5-fluorocytosine (5-FC) as a prodrug.First of all, we tried to develop a way of selective transfection of GFP (green fluorescent protein) gene-containing plasmid DNA, using cationic lipids or calcium phosphate precipitation method. In spite of trials under the various conditions, we did not find any conditions for selective transfection to the virus-infected cells. Therefore, a new method is needed to pursue the above issue. It might be possible to utilize measles virus antibody conjugated with plasmid DNA or measles virus minigenome containing CD gene which can express only in measles virus-infected cells. The latter system is now under investigation.On the other hand, in order to develop assessment system for effect of the gene therapy, pseudovirions prepared from SSPE virus-infected cells by treating with cytochalasin D were infected intracerebrally in young hamsters. The SSPE virus Osaka-1, -2, and -3 strains showed strong neurovirulence ; all hamsters became ill by inoculation of less than one hundred plaque forming units from four to sixteen days and most died within 1-2 weeks after onset. Therefore, estimation of the gene therapy was possible to work.

亚急性硬化性全脑炎（SSPE）是儿童和青少年中枢神经系统的一种进行性和退行性疾病。它是由麻疹病毒在急性期侵入后缓慢感染引起的。SSPE是罕见的，但致命的;没有治愈的治疗尚未建立。我们计划选择性地转染含E.首先，我们尝试了阳离子脂质体法和磷酸钙沉淀法选择性转染含GFP（绿色荧光蛋白）基因的质粒DNA。尽管在各种条件下进行了试验，但我们没有发现选择性转染病毒感染细胞的任何条件。因此，需要一种新的方法来解决上述问题。有可能利用麻疹病毒抗体与质粒DNA或含有CD基因的麻疹病毒小基因组偶联，而CD基因仅在麻疹病毒感染细胞中表达。另一方面，为了开发基因治疗效果的评估系统，通过细胞松弛素D处理从SSPE病毒感染的细胞制备的假病毒体被脑内感染到年轻仓鼠中。SSPE病毒Osaka-1、Osaka-2和Osaka-3株表现出较强的神经毒力，所有仓鼠在接种不到100个空斑形成单位后4 ~ 16天发病，大多数在发病后1-2周内死亡。因此，估计基因治疗是可行的。