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。

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557020/
• 关键词: recombinant Seiidai virus vector; gene therapy; FGF-2; VEGF; HGF; critical limb ischemia; レンチウイルスベクター; 肺高血圧症; 網膜色素変性症; 血管新生; 慢性関節リウマチ; センダイウイルス; 嚢胞性線維症

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于仙台病毒（重组仙台病毒：SeV）的基因转移载体。当前项目的目的是澄清；1) SeV可能的靶器官；2)SeV在体内的生物学行为；3)小动物临床基因治疗的原理研究证明。在呼吸系统中，与腺病毒载体相比，SeV获得了惊人的高基因转移效率（Nature biotechnology 2000）。使用该系统，我们证明了sev介导的靶向气道上皮的白介素-10 （IL-10）基因转移有效地抑制了小鼠移植后纤维性气道闭塞（gene Ther 2003）。关于SeV在治疗性血管生成方面的应用，与基于质粒或SeV介导的血管内皮生长因子基因转移相比，表达碱性成纤维细胞生长因子（bFGF/FGF-2）的SeV在小鼠重度肢体缺血中不断显示出更高的治疗潜力。这种高疗效取决于内源性VEGF和肝细胞生长因子的活性（Circ Res 2002(2)）。此外，SeV-FGF2不仅可以增加慢性肢体缺血时的血液灌注，还可以限制静脉移植物的内膜增生（Am J Physiol 2003, in press）。在此基础上，提出了SeV-FGF2基因治疗重度肢体缺血患者的临床方案。这已经通过了机构审查委员会，现在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-FGF2已经准备好，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，我们发现在目前可用的载体中，SeV是将基因转移到CD34阳性造血干细胞的最有效载体（gene Therapy 2003）。显然，目前的项目不仅在基础实验研究中完成了高质量的工作，而且为SeV的临床应用提供了一个有希望的策略。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中。少

项目成果

Hasegawa H, et al.: "Preclinical and therapeutic utility of HVJ-liposomes as a gene transfer vector for hepatocellular carcinoma using herpes simplex thymidine kinase"Cancer Gene Therapy. 8. 252-258 (2001)

Hasekawa H等人：“HVJ-脂质体作为使用单纯疱疹胸苷激酶的肝细胞癌基因转移载体的临床前和治疗效用”癌症基因治疗。

Takeushi K, et al.: "A simultaneous resection of a concomitant abdominal aortic aneurysm and hepatocellular carcinoma : two cases"Int Surg. 85. 152-157 (2000)

Takeushi K 等人：“同时切除并发腹主动脉瘤和肝细胞癌：两个病例”Int Surg。

Ishida M, et al.: "Immunohistochemical phenotypic alterations of rabbitt autologous vein grafts implanted under arterial circulation with or without poor distal runoff-implications of vein graft remodeling"Atherosclerosis. 154. 345-354 (2001)

Ishida M 等人：“动脉循环下植入的兔自体静脉移植物的免疫组织化学表型改变，有或没有静脉移植物重塑的远端径流不良影响”动脉粥样硬化。

Teramoto N, et al.: "Dual action of ZD6169, a novel K+ channel opener, on ATP-sensitive K+ channels in pig urethral myocytes."The British Journal of Pharmacology. 132(in press). (2001)

Teramoto N 等人：“ZD6169（一种新型 K 通道开放剂）对猪尿道肌细胞 ATP 敏感 K 通道的双重作用。”英国药理学杂志。

Ishida M, et al.: "Immunohistochemical phenotypic alterations of rabbit autologous vein grafts implanted under arterial circulation with or without poor distal runoff-implications of vein graft remodeling"Atherosclerosis. 154. 345-354 (2001)

Ishida M 等人：“动脉循环下植入的兔自体静脉移植物的免疫组织化学表型改变，有或没有静脉移植物重塑的远端径流不良影响”动脉粥样硬化。