腫瘍の特異的標的化を目指した遺伝子治療法の開発

• 研究課題/領域番号: 06283227
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 研究機関: 札幌医科大学 (1999); (財)癌研究会 (1994-1998)
• 研究代表者: 濱田 洋文 札幌医科大学, 医学部, 教授 (00189614)
• 研究分担者: 角田 力弥 福島県立医大, 解剖学2, 助教授 (40045779) ; 山口 聡 (山口 聰) 財団法人癌研究會, 癌化学療法センター・分子生物治療研究部, 研究員 (00280628) ; 花田 賢一 財団法人癌研究會, 癌化学療法センター・分子生物治療研究部, 研究員 (70280625) ; 中村 佳子 財団法人癌研究會, 癌化学療法センター・分子生物治療研究部, 研究員
• 研究期間 (年度): 1999
• 研究課題ステータス: 完了 (1999年度)
• 配分額: 88,000千円 (直接経費: 88,000千円); 1999年度: 15,000千円 (直接経費: 15,000千円); 1998年度: 15,000千円 (直接経費: 15,000千円); 1997年度: 15,000千円 (直接経費: 15,000千円); 1996年度: 15,000千円 (直接経費: 15,000千円); 1995年度: 14,000千円 (直接経費: 14,000千円); 1994年度: 14,000千円 (直接経費: 14,000千円)
• キーワード: adenoviral vector / cancer gene therapy / fiber mutant / integrin / melanoma / melanocyte stimutating hormone / malignant melanoma / gastrin releasing peptide / 遺伝子治療 / アデノウイルスベクター / 腫瘍抑制遺伝子 / 悪性神経膠腫 / 脳腫瘍 / 悪性黒色腫 / EIA / p53 / 免疫制御 / T細胞活性化 / アポトーシス / ファイバー / グリオーマ / 免疫遺伝子治療 / 自殺遺伝子導入療法 / レトロウイルス / アデノウイルス / 抗原提示細胞 / 癌免疫 / サイトカイン遺伝子 / サイトカイン / 腫瘍ワクチン / GM-CSF / IL-4 / レトロウイルス・ベクター / CD82 / ウイルスベクター / 腫瘍ワクチン療法 / 養子免疫療法 / 樹状細胞

研究概要

当研究では、細胞側の受容体分子との吸着を担うファイバータンパクに変異を導入することによって、癌細胞の標的化が可能な変異アデノウイルスベクター、Adv-F/K20、Adv-F/MSH、Adv-F/GRP、Adv-F/RGD、Adv-F40Sなどを作成した。
ファイバーに20個のリジンを付加したF/K20変異型は、ヒト脳腫瘍の対して従来型に比べて数十倍高い遺伝子導入効率が得られ、動物実験でも著明な治療効果増強を示した。これをp53プラスp33ING1によるアポトーシス誘導治療に応用したり、腫瘍特異的な制限増幅型のベクターと組み合わせて、グリオーマに高い治療効果が得られることを報告し、脳外科のグループと協力して、F/K20を用いた臨床研究を準備している。
悪性黒色腫、口腔癌などでは、アデノウイルスの受容体CARの発現がきわめて低く、従来型のアデノウイルスベクターでは遺伝子導入効率が非常に低い。これに対し、メラノサイト刺激ホルモン(MSH)を融合させたF/MSH変異ウイルスは、ヒト悪性黒色腫に従来型よりも十倍程度高い遺伝子導入効率を示した。ガストリン放出ペプチド(GRP)を融合させたF/GRP変異ウイルスは、GRP受容体を高発現するヒト前立腺癌などに高い遺伝子導入効率を示した。一方、インテグリンを標的としたRGDモチーフをファイバーのHIループに含むF/RGDウイルスを用いると、悪性黒色腫、口腔の扁平上皮癌などに従来型に比べて数十倍高い遺伝子導入効率が得られることがわかり、臨床への応用が有望である。
また、通常用いられるヒト5型アデノウイルス(Ad5)のファイバーのみを40型の短ファイバーに置き換えたAdv-F40Sベクターは、Ad5のファイバーの受容体CARと結合しない。現在、Adv-F40Sベクターをベースとして各種のリガンドとの組み合わせによって、宿主細胞域の狭まった特異性の高い「がん標的化ウイルスベクター」の作成を目指している。

研究成果

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