| Co-Investigator(Kenkyū-buntansha) |
ISHIBASHI Tatsuro Kyushu Univ. Grad. School Med. Sci., Prof., 大学院・医学研究院, 教授 (30150428)
NAKASHIMA Yutaka Kyushu Univ. Grad. School Med. Sci., Associate Prof., 大学院・医学研究院, 助教授 (50135349)
SUEISHI Katsuo Kyushu Univ. Grad. School Med. Sci., Prof., 大学院・医学研究院, 教授 (70108710)
NAKAGAWA Kazunori Kyushu Univ. Grad. School Med. Sci., Senior Assist. Prof., 大学院・医学研究院, 講師 (50217668)
EGASHIRA Kensuke Kyushu Univ. Grad. School Med. Sci., Senior Assist. Prof., 大学院・医学研究院, 講師 (60260379)
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| Research Abstract |
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
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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
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