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Non-invasive gene therapy for inherited neurodegenerative disorders (How to cross the BBB?)

遗传性神经退行性疾病的非侵入性基因治疗（如何跨越血脑屏障？）

基本信息

批准号：
17390305
负责人：
SHIMADA Takashi
金额：
$ 10.5万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

The feasibility of non-invasive gene therapy for inherited neurodegenerative disorders like metachromatic leuko dystrophy (MLD) has been investigated. Mannose-6-phosphate receptor (M6PR) plays important roles in both corss-correction and transcytosis across the blood brain barrier of lysosomal enzymes. M6PR is a multifunctional cell surface receptor which also interacts with insulin-like growth factor II (IGF-II) and is composed of 15 repeated domains. We have cloned 7.6kb M6PR cDNA and constructed a series of minigenes. The 4.8kb minigene containing domain 1 to 9 was shown to bind M6P but not IGF-II. Using a lentiviral vector containing the 4.8kb minigene, M6PR can be expressed in various cell lines and tissues of animal models. M6PR expression vector should be useful for studying subcellular localization and trafficking of lysosomal enzymes and for enhancing the efficacy of enzyme replacement therapy for lysosomal disorders. In an alternative approach, we examined the feasibility of intrathecal (IT) injection of adeno-associated viral vector serotype 1 (AAV1) to treat MLD. AAV1 vector expressing arylsulfatase A (ASA) or green fluorescence protein (GFP) was intrathecally injected into ASA knockout MLD model mice. Broad distribution of GFP expression was seen throughout the brain. In addition, a large number of nerve fibers in the dorsal spinal cord and many neural cell bodies in the dorsal root ganglia were efficiently transduced. Widespread distribution of ASA activity and significant reduction of sulfatide content were confirmed in treated MLD model mice. IT injection of AAV1 vector is a useful and noninvasive method for widespread gene delivery to the brain and dorsal root ganglia.

研究了非侵入性基因治疗遗传性神经退行性疾病如异染性脑白质营养不良(MLD)的可行性。甘露糖-6-磷酸受体(M6PR)在溶酶体酶的跨血脑屏障的纠正和跨细胞转运中起着重要作用。M6PR是一种多功能的细胞表面受体，与胰岛素样生长因子II(IGF-II)相互作用，由15个重复结构域组成。我们克隆了7.6kb的M6PR基因，并构建了一系列微型基因片段。含有结构域1-9的4.8kb微型基因可以结合M6P，但不能结合IGF-II。利用含有4.8kb微型基因的慢病毒载体，M6PR可以在动物模型的各种细胞系和组织中表达。M6PR表达载体可用于研究溶酶体酶的亚细胞定位和转运，提高溶酶体病的酶替代治疗效果。在另一种方法中，我们研究了鞘内注射1型腺相关病毒载体(AAV1)治疗MLD的可行性。将表达芳基硫酸酯酶A(AsA)或绿色荧光蛋白(GFP)的AAV1载体注入AsA基因敲除的MLD模型小鼠的鞘内。GFP的表达广泛分布在整个大脑中。此外，背髓内大量神经纤维和背根神经节中的许多神经细胞体也得到了有效的转导。MLD模型小鼠体内AsA活性分布广泛，硫脂含量显著降低。IT注射AAV1载体是一种有用的、非侵入性的方法，可以将基因广泛地输送到脑和背根神经节。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An asymptomatic heterozygous female with fabry disease : implications for enzyme replacement therapy.

患有法布里病的无症状杂合女性：对酶替代疗法的影响。

DOI：
发表时间：
2005
期刊：
J.Nippon Med.Sch. 72
影响因子：
0
作者：
Inagki,S.;et al.
通讯作者：
et al.

Efficient gene transfer via retrograde transport in rodent and primatebrains by an HIV-1-based vector pseudotyped with rabies virusglycoprotein.

通过用狂犬病病毒糖蛋白假型化的基于 HIV-1 的载体在啮齿动物和灵长类动物脑中通过逆行运输进行有效的基因转移。

DOI：
发表时间：
2007
期刊：
Hum Gene Ther 18
影响因子：
0
作者：
Kato S;Inoue K;Kobayashi K;Yasoshima Y;Miyachi S;Inoue S;Hanawa H;Shimada T;Takada M;Kobayashi K
通讯作者：
Kobayashi K

Neuronal specificity of α-synuclein toxicity and effect of parkinco-expression in primates.

灵长类动物中 α-突触核蛋白毒性的神经元特异性和 Parkinco 表达的影响。

DOI：
发表时间：
2007
期刊：
Neuroscience 144
影响因子：
0
作者：
Yasuda T;Miyachi S;Kitagawa R;Wada K;Nihira T;Ren Y-R;Hirai Y;Ageyama N;Terao K;Shimada T;Takada M;Mizuno Y;Mochizuki H
通讯作者：
Mochizuki H

AAV1 mediated co-expression of formylglycine-generating enzyme and arylsulfatase A efficiently corrects sulfatide storage in a mouse model of mitachromatic leukodystrophy

AAV1 介导的甲酰甘氨酸生成酶和芳基硫酸酯酶 A 的共表达可有效纠正偏染性脑白质营养不良小鼠模型中硫苷脂的储存