Delivery of Therapeutic Enzymes and Genes to the CNS
将治疗酶和基因递送至中枢神经系统
基本信息
- 批准号:6615852
- 负责人:
- 金额:$ 23.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-04-01 至 2006-03-31
- 项目状态:已结题
- 来源:
- 关键词:Krabbe's disease Lentivirus behavior test biotherapeutic agent blood brain barrier central nervous system enzyme activity gene delivery system gene expression gene therapy genetically modified animals glucosylceramidase histopathology human immunodeficiency virus 1 immunocytochemistry laboratory mouse laboratory rat magnetic resonance imaging peripheral nervous system polymerase chain reaction positron emission tomography transfection /expression vector western blottings
项目摘要
DESCRIPTION (provided by applicant):
Owing to the structural and functional complexity and relative inaccessibility of the central nervous system (CNS), most chronic neurologic and neurodegenerative disorders lack effective treatments, and, therefore, require the development of novel therapeutic approaches including gene therapy and cellular therapy. Krabbe disease, or globoid cell leukodystrophy (GLD), is an inherited, recessive disorder affecting the peripheral nervous system (PNS) and the CNS caused by defects of the lysosomal enzyme galactocerebrosidase (GALC). This enzyme catalyzes the lysosomal hydrolysis of galactosylceramide and galactosylsphingosine (psychosine). The enzyme defect causes a series of pathological changes including demyelination. This autosomal recessive disease affects humans and animals including dogs, mice, and rhesus monkeys. The goal of the proposed project is to explore gene therapy strategies for Krabbe disease using improved lentivirus-based gene and protein delivery strategies. These strategies will initially be tested in rats and later on extended to mice and rhesus monkeys affected with GLD. The Specific Aims are: 1. To modify HIV-l-based lentiviral vectors for improved transgene delivery and expression in the CNS. These vectors will harbor constitutive as well as regulatable promoters. Vectors will be pseudotyped with the vesicular stomatitis virus (VSV)-G glycoprotein. Pseudotypes involving the Mokola virus G glycoprotein will also be tested with a view toward distributing such vectors more globally in the CNS. Vector delivery will be carried out by direct brain injection. 2. To investigate protein transduction mechanisms with a view toward facilitating the global delivery in the CNS of GALC tagged with the transduction domain of HIV-1 TAT, the membrane translocating hydrophobic sequence from fibroblast growth factor or the herpes simplex virus VP22 protein. 3. To use lentiviral vectors to transfer the GALC cDNA into the brains of mice and rhesus monkeys affected with GLD to evaluate the capacity of such vectors to correct the GLD defect and histological abnormalities.
描述(由申请人提供):
由于中枢神经系统(CNS)的结构和功能复杂性以及相对难以接近,大多数慢性神经系统和神经退行性疾病缺乏有效的治疗方法,因此需要开发新的治疗方法,包括基因治疗和细胞治疗。克拉伯病或球状细胞脑白质营养不良 (GLD) 是一种影响周围神经系统 (PNS) 和 CNS 的遗传性隐性疾病,由溶酶体酶半乳糖脑苷酶 (GALC) 缺陷引起。该酶催化半乳糖神经酰胺和半乳糖基鞘氨醇(精神鞘氨醇)的溶酶体水解。酶缺陷会引起脱髓鞘等一系列病理变化。这种常染色体隐性遗传病影响人类和动物,包括狗、小鼠和恒河猴。拟议项目的目标是利用改进的基于慢病毒的基因和蛋白质递送策略探索克拉伯病的基因治疗策略。这些策略最初将在大鼠中进行测试,随后将扩展到受 GLD 影响的小鼠和恒河猴。具体目标是: 1. 修饰基于 HIV-1 的慢病毒载体,以改善中枢神经系统中的转基因递送和表达。这些载体将含有组成型和可调节的启动子。载体将用水疱性口炎病毒 (VSV)-G 糖蛋白进行假型化。涉及莫科拉病毒 G 糖蛋白的假型也将进行测试,以期在中枢神经系统中更广泛地分布此类载体。载体递送将通过直接脑注射进行。 2. 研究蛋白质转导机制,以促进标记有 HIV-1 TAT 转导结构域、来自成纤维细胞生长因子或单纯疱疹病毒 VP22 蛋白的膜转位疏水序列的 GALC 在 CNS 中的整体递送。 3.利用慢病毒载体将GALC cDNA转入GLD小鼠和恒河猴脑内,评价该载体纠正GLD缺陷和组织学异常的能力。
项目成果
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{{ truncateString('JAKOB REISER', 18)}}的其他基金
Delivery of Therapeutic Enzymes and Genes to the CNS
将治疗酶和基因递送至中枢神经系统
- 批准号:
6721401 - 财政年份:2003
- 资助金额:
$ 23.61万 - 项目类别:
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