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Deveelopment of Novel Gene Theray Strategies Using Recombinant Sendai Virus.

使用重组仙台病毒开发新的基因治疗策略。

基本信息

批准号：
12557020
负责人：
YONEMITSU Yoshikazu
金额：
$ 8.19万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

We recently developed a novel gene transfer vector, based on Sendai virus (recombinant Sendai virus: SeV). Aims of the current project were to clarify; 1) possible target organs of SeV, 2) biological behavior of the SeV in vivo, and 3) proof of principle studies for clinical gene therapy using small animals.In respiratory system, SeV achieved amazingly high gene transfer efficiency compared to adenoviral vectors (Nature Biotechnol 2000). Using this system, we demonstrated that SeV-mediated interleukin-10 (IL-10) gene transfer targeted to the airway epithelium efficiently inhibited post transplantation fibrous airway obliteration in mice (Gene Ther 2003).Regarding the application of SeV for therapeutic angiogenesis, SeV expressing basic fibroblast growth factor (bFGF/FGF-2) constantly showed higher therapeutic potentials in murine critical limb ischemia, compared to that seen using plasmid-based or SeV-mediated vascular endothelial growth factor gene transfer, which has been used for cl … More inical trials in United Stales (Circ Res 2002(1)), This high therapeutic effect depended on the endogenous VEGF and hepatocyte growth factor activities (Circ Res 2002 (2)). Further, SeV-FGF2 was also effective not only to increase blood perfusion in chronic limb ischemia but also to limit intimal hyperplasia of vein grafts (Am J Physiol 2003, in press).Based on these findings, clinical protocol of SeV-FGF2 gene therapy to treat patients with critical limb ischemia was proposed. This already passed Institutional Review Board, and is now under evaluation by governmental review board. Clinical grade SeV-FGF2 based on good manufacturing practice (GMP) was already prepared, thus this clinical study will be started in 2003.Further, we demonstrated high gene transfer efficiencies of SeV in vessel wall (FASEB J 2001), retinal pigment epithelium (Exp Eye Res 2002), activated T-lymphocytes (Gene Therapy 2003, in press). In addition, we found that SeV was the most efficient vehicle for gene transfer to CD34 positive hematopoietic stem cells among the currently available vectors (Gene Therapy 2003).Clearly, the current project performed not only high quality works in basic experimental studies, but also suggested a hopeful clinical strategy using SeV.We will extend these findings obtained in this project to more feasible and more effective gene therapy. Less

我们最近开发了一种新的基因转移载体，基于仙台病毒（重组仙台病毒：SeV）。本项目的目的是阐明：1）SeV的可能靶器官，2）SeV在体内的生物学行为，以及3）使用小动物的临床基因治疗的原理研究的证明。在呼吸系统中，与腺病毒载体相比，SeV实现了惊人的高基因转移效率（Nature Biotechnol 2000）。利用该系统，我们证明SeV介导的靶向气道上皮的白细胞介素-10（IL-10）基因转移有效地抑制小鼠移植后纤维性气道闭塞关于SeV用于治疗性血管生成的应用，表达碱性成纤维细胞生长因子的SeV与使用基于质粒或SeV介导的血管内皮生长因子基因转移相比，bFGF/FGF-2在小鼠严重肢体缺血中不断显示出更高的治疗潜力，已用于CL ...更多信息美国的临床试验（Circ Res 2002（1）），这种高治疗效果取决于内源性VEGF和肝细胞生长因子活性（Circ Res 2002（2））。此外，SeV-FGF 2不仅对增加慢性肢体缺血的血液灌注，而且对限制静脉移植物的内膜增生也是有效的（Am J Physiol 2003，出版中）。这已经通过了机构审查委员会，目前正在接受政府审查委员会的评估。基于良好生产规范（GMP）的临床级SeV-FGF 2已经制备，因此本临床研究将于2003年开始。此外，我们证明了SeV在血管壁（FASEB J 2001）、视网膜色素上皮（Exp Eye Res 2002）、活化的T淋巴细胞（Gene Therapy 2003，in press）中的高基因转移效率。此外，我们发现SeV是目前可用的载体中最有效的基因转移到CD 34阳性造血干细胞的载体（Gene Therapy 2003）。显然，本项目不仅在基础实验研究中进行了高质量的工作，而且还提出了使用SeV的有希望的临床策略。我们将在本项目中获得的这些发现扩展到更可行和更有效的基因治疗。少