2002 Fiscal Year Annual Research Report

組み換え型センダイウイルスベクターによる遺伝子治療系の確立とその臨床応用〜国産新規遺伝子導入ベクターによる世界初の遺伝子治療臨床応用を目指して〜

Research Project

Project/Area Number	12557020
Research Institution	KYUSHU UNIVERSITY
Principal Investigator	米満吉和九州大学, 医学部附属病院, 助手 (40315065)
Co-Investigator(Kenkyū-buntansha)	石橋達朗九州大学, 大学院・医学研究院, 教授 (30150428) 中島豊九州大学, 大学院・医学研究院, 助教授 (50135349) 居石克夫九州大学, 大学院・医学研究院, 教授 (70108710) 中川和憲九州大学, 大学院・医学研究院, 講師 (50217668) 江頭健輔九州大学, 大学院・医学研究院, 講師 (60260379)
Keywords	センダイウイルスベクター / 遺伝子治療 / FGF-2 / VEGF / HGF / 重症虚血肢
Research Abstract	本研究最終年度にあたり、これまで明らかにして来た国産新規遺伝子導入ベクター(センダイウイルスベクター:SeV)の生体内動態、遺伝子導入能に関する情報を発展し、種々の治療実験を進めた。呼吸器ではSeVの特筆すべき気道上皮への遺伝子導入を利用し(Nature Biotechnol 2000)、肺移植後細気管支炎へのIL-10遺伝子導入の効果を検証した。SeVによりIL-10効率よく気道局所で発現し、気道閉塞が効果的に抑制できることを示した(Gene Ther 2003)。本ベクターによるFGF-2遺伝子導入は、欧米で臨床試験が進んでいるVEGFと比較して、重症虚血肢において安全かつ高い効果が得られることを証明した(Circ Res 2002(1))。さらにこのFGF-2の効果は内因性HGFの発現により確保されていることを証明した(Circ Res 2002(2))。FGF-2は自家静脈グラフト内膜肥厚も抑制することが明らかになり、適応疾患の選択を広げることが可能である(Am J Physiol, in press)。以上のデータをもとに、本遺伝子治療臨床研究プロトコールは九州大学倫理委員会の承認を得ており、現在厚生労働省の審査中である。2003年中には臨床試験を開始する予定である。その他、眼球網膜では網膜色素上皮細胞へ高い遺伝子導入効率が得られることを証明した(Exp Eye Res 2002)。さらに遺伝子治療のよいターゲットとされるヒトCD34陽性造血幹細胞(Gene Ther 2003)や活性化T細胞などの血球系細胞(Gene Ther, in press)にも既存のベクターを遥かに凌駕する遺伝子導入が可能であることを証明した。以上のように本研究計画は3年間の期間で予想以上の成果をおさめ、一部では臨床研究に入る系も構築できた。今後はさらに多くの疾患モデルに対し治療実験を進め、諸臓器を対象とした難治姓疾患への新しい遺伝子治療臨床応用への可能性を模索したい。

Research Products

(44 results)

All Other

All Publications (44 results)

[Publications] Yonemitsu Y, et al.: "Efficient gene transfer to the airway epithelium using recombinant Sendai virus"Nature Biotechnology. 18. 970-973 (2000)
[Publications] Teramoto N, et al.: "The effects of caffeine on ATP-sensitive K+ currents in smooth muscle cells from pig urethra"British Journal Pharmacology. 131. 515-523 (2000)
[Publications] 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)
[Publications] Masaki I, et al.: "Recombinant Sendai Virus-mediated Gene Transfer to Vasculature : a new class of efficient gene transfer vector to the vascular system"The FASEB Journal. 15. 1294-1296 (2001)
[Publications] Teramoto N, et al.: "Dual action of ZD6169, a novel K+ channel opener, on ATP-sensitive K+ channels in pig urethral myocytes"British Journal Pharmacology. 133. 154-164 (2001)
[Publications] Komori k, et al.: "Non-penetrating vascular clips anastomosis inhibited intimal thickening under poor runoff conditions in canine autogenous vein grafts"European Journal of Vascular and Endovascular Surgery. 21. 241-247 (2001)
[Publications] 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)
[Publications] Koga T, et al.: "Heterogenous distribution of p53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with p53 gene mutation"International Journal of Cancer. 95. 232-239 (2001)
[Publications] Koga T, et al.: "Clinico-pathological and molecular evidence indicating the independency of bronchio-alveolar components from other subtypes of human lung adenocarcinoma"Clinical Cancer Research. 7. 1730-1738 (2001)
[Publications] Matsumoto T, et al.: "Successful and optimized in vivo gene transfer to rabbit carotid artery mediated by electronic pulse"Gene Therapy. 8. 1174-1179 (2001)
[Publications] Yamashita A, et al.: "Fibroblast growth factor-2 determines severity of joint disease in adjuvant-induced arthritis in rats"The Journal of Immunology. 168. 450-457 (2002)
[Publications] Kume M, et al.: "Administration of a decoy against the AP-1 binding site suppresses neointimal thickening in rabbit balloon injured arteries"Circulation. 105. 1226-1232 (2002)
[Publications] Ikeda Y, et al.: "Recombinant Sendai virus-mediated gene transfer to the retinal tissue of adult rats : efficient gene transfer by brief exposure"Experimental Eye Research. 75. 39-48 (2002)
[Publications] Koga T, et al.: "Lung adenocarcinoma with bronchio-alveolar carcinoma component frequently associates foci of high grade atypical adenomatous hyperplasia"American Journal of Clinical Pathology. 117. 464-470 (2002)
[Publications] Ohta S, et al.: "Intraluminal gene transfer of endothelial nitric oxide synthase partially supresses neointimal formation of vein grafts of hypercholesterolemic rabbits : a limited biological effect as a result of the loss of medial smooth muscle cells"Surgery. 131. 644-653 (2002)
[Publications] Masaki I, et al.: "Gene therapy for experimental critical limb ischemia : acceleration of limb loss by overexpression of VEGF165, but not of FGF-2"Circulation Research. 90. 966-973 (2002)
[Publications] Jiang C, et al.: "Gene transfer into brain capillary endothelial cells in vitro and in vivo with HVJ-liposomes"The Journal of Drug Targeting. 10. 345-352 (2002)
[Publications] Kanna T, et al.: "Effects of sevoflurane on bradykinin-induced calcium mobilization in pulmonary arterial valvular endothelial cells in situ : Sevoflurane Stimulates Plasmalemmal Calcium Influx Into Endothelial Cells"The Journal of Cardiovascular Pharmacology. 40. 714-724 (2002)
[Publications] Takeuchi K, et al.: "A simultaneous resection of a concomitant abdominal aortic aneurysm and hepatocellular carcinoma : two cases"Int Surg. 85. 152-157 (2000)
[Publications] 真崎一郎, 他: "特集:循環器疾患への遺伝子治療 3.冠動脈疾患に対する遺伝子治療"医学のあゆみ. 192. 213-217 (2000)
[Publications] 米満吉和, 他: "シンポジウム「動脈硬化と炎症」感染寄生体とヒト血管病変-病原寄生体は病原因子と成り得るか?"動脈硬化. 27. 179-187 (2000)
[Publications] 米満吉和, 他: "特集:血管炎の基礎と臨床血管炎の基礎:血管炎における閉塞性血管病変の機序"最新医学. 55. 2647-2654 (2000)
[Publications] 米満吉和, 他: "特集:分子診療の現状と将来 3.平滑筋細胞増殖制御をターゲットとした遺伝子治療"分子心血管病. 1. 252-262 (2000)
[Publications] Sakamoto T, et al.: "Gene targeting to the retina"Advanced Drug Delivery Reviews. 52. 93-102 (2001)
[Publications] Ikeda Y, et al.: "Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Pulmonary Hypertension in Rats"American Journal of Physiology. Heart and Circulatory Physiology. 283. H2021-H2028 (2002)
[Publications] Onimura M. et al.: "FGF-2 gene transfer can stimulate HGF expression irrespective of hypoxia-mediated downregulation in ischemic limb"Circulation Research. 91. 723-730 (2002)
[Publications] Shoji F, et al.: "Airway-directed gene transfer of interleukin-10 using recombinant Sendai virus effectively prevents post-transplantation bronchiolitis obliterans in mice"Gene Therapy. 10. 213-218 (2003)
[Publications] Jin CH, et al.: "Recombinant Sendai virus provides a highly efficient gene transfer into human cord blood-derived hematopoietic stem cells"Gene Therapy. 10. 272-280 (2003)
[Publications] Sugimachi Keishi, et al.: "A conservative treatment for the removal of a central venous catheter with large thrombus : a case report"Nutrition in Clinical Ptactice. 15. 223-226 (2000)
[Publications] Nakagawa K, et al.: "Angiogenesis and its regulation : roles of vascular endothelial cell growth factor"Seminars in Thrombosis and Hemostasis. 26. 61-66 (2000)
[Publications] 庄司文裕, 他: "組換えセンダイウイルスベクターを用いた血管壁への遺伝子導入"脳と循環. 7. 52-56 (2002)
[Publications] 米満吉和, 他: "特集「大動脈炎症候群をどう診るか」 10.ウイルス感染と血管炎"Heart View. 6. 88-93 (2002)
[Publications] 米満吉和, 他: "Suggestion:「機能的」血管新生療法の確立に向けて。"治療学. 36. 471 (2002)
[Publications] 米満吉和, 他: "血管新生遺伝子治療における「血管新生因子作用機構の階層性」と「"Integrated" Therapeutic Angiogenesis」の提唱"脈管学. 42. 381-389 (2002)
[Publications] 山下彰久, 他: "特集「血液細胞と血管新生」 8.遺伝子導入による血管新生療法"血液フロンティア. 12. 803-811 (2002)
[Publications] 宮崎勝徳, 他: "特集:遺伝子治療-現状とその近未来。遺伝子治療前臨床研究の現状:14.センダイウイルスベクター組換えセンダイウイルスベクターによる遺伝子治療臨床研究計画"医学のあゆみ. 203. 564-569 (2002)
[Publications] 米満吉和, 他: "わだい:サイトメガロウイルスと動脈硬化"Medical Technology. 29. 386-388 (2001)
[Publications] 居石克夫, 他: "血管壁細胞の遺伝子発現制御と治療への応用"脈管学. 41. 501-509 (2001)
[Publications] 米満吉和, 他: "ウイルス感染と大型血管炎"脈管学. 41. 381-390 (2001)
[Publications] 坂本泰二, 他: "網膜への遺伝子ターゲティング(Gene Targeting to Retina)"あたらしい眼科. 18. 41-46 (2001)
[Publications] 真崎一郎, 他: "Trend Paper:組換えセンダイウイルスベクターによる遺伝子治療:純国産ベクターは遺伝子治療に新しい道を開くか?"バイオ・ベンチャー. 1. 85-88 (2001)
[Publications] Yonemitsu Y, et al.: "Gene Therapy in Vascular Surgery Comes of Age"Surgery. 131. S261-S268 (2002)
[Publications] 池田康博, 他: "「医学研究再入門」第5回:個体レベルの遺伝子導入"分子心血管病. 3. 609-614 (2002)
[Publications] Yamaguchi S. et al.: "A traumatic pseudoaneurysm of the dorsalis pedis artery : report of a case"Surg Today. 32. 756-757 (2002)

2002 Fiscal Year Annual Research Report

組み換え型センダイウイルスベクターによる遺伝子治療系の確立とその臨床応用〜国産新規遺伝子導入ベクターによる世界初の遺伝子治療臨床応用を目指して〜

Principal Investigator

米満 吉和 九州大学, 医学部附属病院, 助手 (40315065)

Research Products

[Publications] Yonemitsu Y, et al.: "Efficient gene transfer to the airway epithelium using recombinant Sendai virus"Nature Biotechnology. 18. 970-973 (2000)

[Publications] Teramoto N, et al.: "The effects of caffeine on ATP-sensitive K+ currents in smooth muscle cells from pig urethra"British Journal Pharmacology. 131. 515-523 (2000)

[Publications] 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)

[Publications] Masaki I, et al.: "Recombinant Sendai Virus-mediated Gene Transfer to Vasculature : a new class of efficient gene transfer vector to the vascular system"The FASEB Journal. 15. 1294-1296 (2001)

[Publications] Teramoto N, et al.: "Dual action of ZD6169, a novel K+ channel opener, on ATP-sensitive K+ channels in pig urethral myocytes"British Journal Pharmacology. 133. 154-164 (2001)

[Publications] Komori k, et al.: "Non-penetrating vascular clips anastomosis inhibited intimal thickening under poor runoff conditions in canine autogenous vein grafts"European Journal of Vascular and Endovascular Surgery. 21. 241-247 (2001)

[Publications] 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)

[Publications] Koga T, et al.: "Heterogenous distribution of p53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with p53 gene mutation"International Journal of Cancer. 95. 232-239 (2001)

[Publications] Koga T, et al.: "Clinico-pathological and molecular evidence indicating the independency of bronchio-alveolar components from other subtypes of human lung adenocarcinoma"Clinical Cancer Research. 7. 1730-1738 (2001)

[Publications] Matsumoto T, et al.: "Successful and optimized in vivo gene transfer to rabbit carotid artery mediated by electronic pulse"Gene Therapy. 8. 1174-1179 (2001)

[Publications] Yamashita A, et al.: "Fibroblast growth factor-2 determines severity of joint disease in adjuvant-induced arthritis in rats"The Journal of Immunology. 168. 450-457 (2002)

[Publications] Kume M, et al.: "Administration of a decoy against the AP-1 binding site suppresses neointimal thickening in rabbit balloon injured arteries"Circulation. 105. 1226-1232 (2002)

[Publications] Ikeda Y, et al.: "Recombinant Sendai virus-mediated gene transfer to the retinal tissue of adult rats : efficient gene transfer by brief exposure"Experimental Eye Research. 75. 39-48 (2002)

[Publications] Koga T, et al.: "Lung adenocarcinoma with bronchio-alveolar carcinoma component frequently associates foci of high grade atypical adenomatous hyperplasia"American Journal of Clinical Pathology. 117. 464-470 (2002)

[Publications] Ohta S, et al.: "Intraluminal gene transfer of endothelial nitric oxide synthase partially supresses neointimal formation of vein grafts of hypercholesterolemic rabbits : a limited biological effect as a result of the loss of medial smooth muscle cells"Surgery. 131. 644-653 (2002)

[Publications] Masaki I, et al.: "Gene therapy for experimental critical limb ischemia : acceleration of limb loss by overexpression of VEGF165, but not of FGF-2"Circulation Research. 90. 966-973 (2002)

[Publications] Jiang C, et al.: "Gene transfer into brain capillary endothelial cells in vitro and in vivo with HVJ-liposomes"The Journal of Drug Targeting. 10. 345-352 (2002)

[Publications] Kanna T, et al.: "Effects of sevoflurane on bradykinin-induced calcium mobilization in pulmonary arterial valvular endothelial cells in situ : Sevoflurane Stimulates Plasmalemmal Calcium Influx Into Endothelial Cells"The Journal of Cardiovascular Pharmacology. 40. 714-724 (2002)

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

[Publications] 真崎一郎, 他: "特集:循環器疾患への遺伝子治療 3.冠動脈疾患に対する遺伝子治療"医学のあゆみ. 192. 213-217 (2000)

[Publications] 米満吉和, 他: "シンポジウム「動脈硬化と炎症」 感染寄生体とヒト血管病変-病原寄生体は病原因子と成り得るか?"動脈硬化. 27. 179-187 (2000)

[Publications] 米満吉和, 他: "特集:血管炎の基礎と臨床 血管炎の基礎:血管炎における閉塞性血管病変の機序"最新医学. 55. 2647-2654 (2000)

[Publications] 米満吉和, 他: "特集:分子診療の現状と将来 3.平滑筋細胞増殖制御をターゲットとした遺伝子治療"分子心血管病. 1. 252-262 (2000)

[Publications] Sakamoto T, et al.: "Gene targeting to the retina"Advanced Drug Delivery Reviews. 52. 93-102 (2001)

[Publications] Ikeda Y, et al.: "Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Pulmonary Hypertension in Rats"American Journal of Physiology. Heart and Circulatory Physiology. 283. H2021-H2028 (2002)

[Publications] Onimura M. et al.: "FGF-2 gene transfer can stimulate HGF expression irrespective of hypoxia-mediated downregulation in ischemic limb"Circulation Research. 91. 723-730 (2002)

[Publications] Shoji F, et al.: "Airway-directed gene transfer of interleukin-10 using recombinant Sendai virus effectively prevents post-transplantation bronchiolitis obliterans in mice"Gene Therapy. 10. 213-218 (2003)

[Publications] Jin CH, et al.: "Recombinant Sendai virus provides a highly efficient gene transfer into human cord blood-derived hematopoietic stem cells"Gene Therapy. 10. 272-280 (2003)

[Publications] Sugimachi Keishi, et al.: "A conservative treatment for the removal of a central venous catheter with large thrombus : a case report"Nutrition in Clinical Ptactice. 15. 223-226 (2000)

[Publications] Nakagawa K, et al.: "Angiogenesis and its regulation : roles of vascular endothelial cell growth factor"Seminars in Thrombosis and Hemostasis. 26. 61-66 (2000)

[Publications] 庄司文裕, 他: "組換えセンダイウイルスベクターを用いた血管壁への遺伝子導入"脳と循環. 7. 52-56 (2002)

[Publications] 米満吉和, 他: "特集「大動脈炎症候群をどう診るか」 10.ウイルス感染と血管炎"Heart View. 6. 88-93 (2002)

[Publications] 米満吉和, 他: "Suggestion:「機能的」血管新生療法の確立に向けて。"治療学. 36. 471 (2002)

[Publications] 米満吉和, 他: "血管新生遺伝子治療における「血管新生因子作用機構の階層性」と「"Integrated" Therapeutic Angiogenesis」の提唱"脈管学. 42. 381-389 (2002)

[Publications] 山下彰久, 他: "特集「血液細胞と血管新生」 8.遺伝子導入による血管新生療法"血液フロンティア. 12. 803-811 (2002)

[Publications] 宮崎勝徳, 他: "特集:遺伝子治療-現状とその近未来。遺伝子治療前臨床研究の現状:14.センダイウイルスベクター組換えセンダイウイルスベクターによる遺伝子治療臨床研究計画"医学のあゆみ. 203. 564-569 (2002)

[Publications] 米満吉和, 他: "わだい:サイトメガロウイルスと動脈硬化"Medical Technology. 29. 386-388 (2001)

[Publications] 居石克夫, 他: "血管壁細胞の遺伝子発現制御と治療への応用"脈管学. 41. 501-509 (2001)

[Publications] 米満吉和, 他: "ウイルス感染と大型血管炎"脈管学. 41. 381-390 (2001)

[Publications] 坂本泰二, 他: "網膜への遺伝子ターゲティング(Gene Targeting to Retina)"あたらしい眼科. 18. 41-46 (2001)

[Publications] 真崎一郎, 他: "Trend Paper:組換えセンダイウイルスベクターによる遺伝子治療:純国産ベクターは遺伝子治療に新しい道を開くか?"バイオ・ベンチャー. 1. 85-88 (2001)

[Publications] Yonemitsu Y, et al.: "Gene Therapy in Vascular Surgery Comes of Age"Surgery. 131. S261-S268 (2002)

[Publications] 池田康博, 他: "「医学研究再入門」第5回:個体レベルの遺伝子導入"分子心血管病. 3. 609-614 (2002)

[Publications] Yamaguchi S. et al.: "A traumatic pseudoaneurysm of the dorsalis pedis artery : report of a case"Surg Today. 32. 756-757 (2002)

米満吉和九州大学, 医学部附属病院, 助手 (40315065)

[Publications] 米満吉和, 他: "シンポジウム「動脈硬化と炎症」感染寄生体とヒト血管病変-病原寄生体は病原因子と成り得るか?"動脈硬化. 27. 179-187 (2000)

[Publications] 米満吉和, 他: "特集:血管炎の基礎と臨床血管炎の基礎:血管炎における閉塞性血管病変の機序"最新医学. 55. 2647-2654 (2000)