Gene therapy for neuronal diseases using rAAV

使用 rAAV 进行神经元疾病的基因治疗

• 批准号: 16390418
• 负责人: OKADA Takashi
• 金额: $ 8.13万
• 依托单位: National Institute of Neuroscience, National Center of Neurology and Psychiatry (2006)Jichi Medical University (2004-2005)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390418/
• 关键词: gene; virus; neuronal diseases; biotechnology; 遺伝子治療; ウイルスベクター; アデノ随判ウイルス; 脳腫瘍; 脳血管障害; 動脈硬化症; IL-10

The adeno-associated virus (AAV) vector is a potentially useful gene transfer vehicle for neurologic gene therapies. The development of novel therapeutic strategies for neurological disorder by using the AAV vector has an increasing impact on gene therapy research. We have developed the production system of the AAV vector and evaluated the utility with various disease models.1. We developed a large-scale method to produce vectors with an active gassing system that uses large culture vessels to process labor-and cost-effective infection or transfection in a closed system.2. Interleukin-10 is an anti-inflammatory cytokine that may modulate the atherosclerotic disease process. Intramuscular injection of AAV5-mIL10 into ApoE-deficient mice inhibited atherogenesis through anti-inflammatory and cholesterol-lowering effects.3. Neuropathological abnormalities associated with Huntington disease, such as insoluble protein accumulation and down-regulation of DARPP-32 expression, were successfully ameliorated in mice by the rAAV-mediated RNAi transduction.4. The use of HDAC inhibitor should enhance the utility of rAAV-mediated transduction strategies for cancer gene therapy. The superior transduction was related to the proposed histone-associated chromatin form of the rAAV concatemer in transduced cells. In the analysis with subcutaneous tumor models, improved transgene expression as well as therapeutic effect was confirmed in vivo.5. We developed genetically-modified mesenchymal stem cells that produce progeny vectors encoding HSV-tk, aiming at further augmenting therapeutic efficacy of systemic suicide cancer gene therapy. The tumor tropism and anti-tumor effects of vector-producing MSCs were confirmed by intravascular injection in tumor-bearing nude mice.

腺相关病毒（AAV）载体是一种潜在的有用的基因转移载体的神经基因治疗。通过使用AAV载体开发新的神经系统疾病治疗策略对基因治疗研究产生了越来越大的影响。我们已经开发了AAV载体的生产系统，并评估了各种疾病模型的效用。我们开发了一种大规模的方法来生产具有主动充气系统的载体，该系统使用大型培养容器在封闭系统中处理劳动力和成本效益高的感染或转染。白细胞介素-10是一种抗炎细胞因子，可以调节动脉粥样硬化疾病的过程。肌肉注射AAV 5-mIL 10可通过抗炎和降胆固醇作用抑制ApoE基因缺陷小鼠动脉粥样硬化的形成.通过rAAV介导的RNAi转导，成功地改善了与亨廷顿病相关的神经病理学异常，如不溶性蛋白积累和DARPP-32表达下调. HDAC抑制剂的使用将增强rAAV介导的转导策略用于癌症基因治疗的效用。该上级转导与转导细胞中rAAV多联体的组蛋白相关染色质形式有关。在皮下肿瘤模型的分析中，体内证实了转基因表达的改善以及治疗效果。我们开发了经遗传修饰的间充质干细胞，其产生编码HSV-tk的子代载体，旨在进一步增强全身性自杀性癌症基因治疗的治疗效果。通过血管内注射荷瘤裸鼠证实了载体产生的MSC的肿瘤嗜性和抗肿瘤作用。

项目成果

Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice

• DOI: 10.1038/sj.gt.3302262
• 发表时间: 2004-07-01
• 期刊: GENE THERAPY
• 影响因子: 5.1
• 作者: Mochizuki, S;Mizukami, H;Kume, A
• 通讯作者: Kume, A

Gene transfer to the rat kidney in vivo and ex vivo using an adenovirus vector:: factors influencing transgene expression

• DOI: 10.1093/ndt/gfh783
• 发表时间: 2005-07-01
• 期刊: NEPHROLOGY DIALYSIS TRANSPLANTATION
• 影响因子: 6.1
• 作者: Fujishiro, J;Takeda, SI;Kobayashi, E
• 通讯作者: Kobayashi, E

Phenotype correction of hemophilia A mice with adeno-associated virus vectors carrying the B domain-deleted canine factor VIII gene

• DOI: 10.1016/j.thromres.2005.11.006
• 发表时间: 2006-01-01
• 期刊: THROMBOSIS RESEARCH
• 影响因子: 7.5
• 作者: Ishiwata, Akira;Mimuro, Jun;Sakata, Yoichi
• 通讯作者: Sakata, Yoichi

ウイルス中空粒子の迅速除去および精製方法

病毒空心颗粒的快速去除纯化方法

• 发表时间: 2005

rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse

• DOI: 10.1016/j.bbrc.2006.02.141
• 发表时间: 2006-04-28
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Machida, Y;Okada, T;Nukina, N
• 通讯作者: Nukina, N