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）载体是神经系统基因疗法的潜在有用的基因转移载体。通过使用AAV载体的神经系统疾病的新型治疗策略的发展对基因治疗研究的影响越来越大。我们已经开发了AAV载体的生产系统，并通过各种疾病模型评估了效用。1。我们开发了一种大规模的方法，以使用活跃的气体系统生产向量，该系统使用大型培养容器处理劳动力和成本效益的感染或转染的媒介。2。白介素10是一种抗炎细胞因子，可能调节动脉粥样硬化疾病过程。肌内注射AAV5-MIL10在缺乏APOE的小鼠中通过抗炎和降低胆固醇的效应抑制了动脉粥样硬化。3。与亨廷顿疾病相关的神经病理异常，例如不溶性蛋白的积累和DARPP-32表达的下调，通过RAAV介导的RNAi转导成功地改善了小鼠。4。 HDAC抑制剂的使用应增强RAAV介导的癌症基因治疗的转导策略的实用性。上转导与转导细胞中RAAV con偶代体的拟议组蛋白相关染色质形式有关。在与皮下肿瘤模型的分析中，在体内证实了转基因表达以及治疗效应的改善。5。我们开发了产生编码HSV-TK的后代载体的遗传改性的间充质干细胞，旨在进一步增强全身自杀癌基因治疗的治疗疗效。通过肿瘤裸鼠的血管内注射证实了产生载体的MSC的肿瘤向向性和抗肿瘤作用。

项目成果

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

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

血中コレステロール濃度低下作用物質

血胆固醇浓度降低剂

• 发表时间: 2004

Adeno-Associated Virus (AAV) vector-mediated liver- and muscle-directed transgene expression using various kinds of promoters and serotypes.

使用各种启动子和血清型的腺相关病毒 (AAV) 载体介导的肝脏和肌肉定向转基因表达。

• 发表时间: 2004
• 期刊: Gene Ther and Mol Biol 8・1
• 作者: Mochizuki S;et al.
• 通讯作者: et al.

IL-10発現AAVベクターを用いた心血管病変の遺伝子治療

使用表达 IL-10 的 AAV 载体进行心血管病变的基因治疗

• 发表时间: 2006
• 期刊: 最新医学. 61・4
• 作者: Ishiwata;A. et al.;岡田尚巳 et al.
• 通讯作者: 岡田尚巳 et al.