Kagoshima University · Graduate School of Medical and Dental Sciences · 助教

Research keywords1型糖尿病・遺伝子治療・HB-EGF/HGF遺伝子治療・アデノウイルス・β細胞保護・再生

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• Kawakami H., Ijichi N., Obama Y., Matsuda E., Mitsui K., Nishikawaji Y., Watanabe M., Nagano S., Taniguchi N., Komiya S., Kosai K.i. . An optimal promoter regulating cytokine transgene express2024 · 記述言語： 英語 掲載種別： 研究論文（学術雑誌） 出版者・発行元： Translational Research In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive “conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)” (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active “cytomegalovirus enhancer and β-actin promoter”, provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active “Rous sarcoma virus long terminal repeat”, not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials. DOI： 10.1016/j.trsl.2024.07.002 Scopus PubMed
• 小戝 健一郎, 西川路 侑耶, 伊集院 広壮, 松田 恵理子, 三井 薫 . 多因子増殖制御型アデノウイルスによる画期的ながん治療 . Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ Ｓｙｓｔｅｍ39 ( 4 ) 248 - 259 2024年9月 詳細を見る 記述言2024 · 記述言語： 日本語 出版者・発行元： 日本DDS学会 非増殖型アデノウイルス（Ad）ベクターが1990年代の<i>in vivo</i>がん遺伝子治療の研究を牽引し、2000年代より腫瘍溶解性ウイルス（OV）の制限増殖型Ad（CRA）の開発が本格化し、近年は免疫遺伝子搭載型CRAの研究と臨床応用が盛んである。筆者らは、複雑に遺伝子改変したCRA（多因子増殖制御型CRA；m-CRA）を多種多様・効率的に作製できるプラットフォーム技術を開発し、サバイビン反応性m-CRA（Surv.m-CRA）を創出した。治療遺伝子未搭載のSurv.m-CRA-1は、治療抵抗性の悪性骨腫瘍への早期承認を目指した多施設共同・第Ⅱ相医師主導治験を現在進めている。さらに最近、安全かつ最大の治療効果を得るための、免疫遺伝子搭載OVにおける「至適プロモーターによる至適発現の必要性」という新概念を見出した。本稿ではAdのウイルス学に続いて上記を概説し、次世代CRAの展望について述べる。 DOI： 10.2745/dds.39.248 Scopus CiNii Research
• Kamizono J., Nishikawaji Y., Nagano S., Ikeda M., Horikawa Y., Kamisasanuki T., Mitsui K., Matsuda E., Kosai K.i. . Triple-regulated conditionally replicating adenovirus for effective and safe2024 · 記述言語： 日本語 出版者・発行元： Biochemical and Biophysical Research Communications There is no effective therapy for peritoneal carcinomatosis derived from gastric cancer. An ideal conditionally replicating adenovirus (CRA) that selectively replicates in and kills cancer cells has not been developed for gastric cancer-derived peritoneal carcinomatosis. Using our platform technology of CRA regulated and treating tumors with multiple factors (m-CRA), we generated two types of survivin-responsive m-CRAs, Surv.m-CRA-CMVp and Surv.m-CRA-CEAp, consisting of E1A downstream of the survivin promoter, and the mutated E1B gene downstream of the human cytomegalovirus immediate early gene enhancer/promoter and carcinoembryonic antigen promoter, respectively. Survivin mRNA was expressed at high and undetectable levels in two gastric cancer cells and eleven normal cells, respectively. Carcinoembryonic antigen was expressed at high and very low levels in MKN-45 gastric cancer and normal PrEC cells, respectively, and was not detected in other cell types. While both Surv.m-CRA-CEAp and Surv.m-CRA-CMVp exhibited potent cytotoxic effects on MKN-45 cells in vitro, Surv.m-CRA-CEAp significantly reduced cytotoxicity to normal cells compared to Surv.m-CRA-CMVp. Control mice that received an intraperitoneal injection of MKN-45 cells gradually lost body weight and died of peritoneal carcinomatosis within 98 days. In contrast, all mice receiving Surv.m-CRA-CEAp or Surv.m-CRA-CMVp-infected MKN-45 cells increased their body weight and survived 120 days. In conclusion, the triple-regulated Surv.m-CRA-CEAp enhances cancer specificity (i.e., safety) without reducing the potent therapeutic effect for carcinoembryonic antigen-positive gastric cancer-derived peritoneal carcinomatosis. The modified E1B promoter strategy of CRA facilitates the development of novel CRAs for the effective and safe treatment of a variety of refractory cancers. DOI： 10.1016/j.bbrc.2024.150894 Scopus PubMed
• Mitsui K. . Optimization of adenoviral gene transfer in human pluripotent stem cells . Biochemical and Biophysical Research Communications541 78 - 82021 · 記述言語： 英語 掲載種別： 研究論文（学術雑誌） 出版者・発行元： Biochemical and Biophysical Research Communications Human pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, have the potential to differentiate into a wide variety of cells in vitro and have applications in basic developmental biology research and regenerative medicine. To understand the process of differentiation from pluripotent stem cells to functional cells, it is necessary to efficiently and safely transfer and express exogenous genes. We attempted to optimize the efficient transfer of genes into pluripotent stem cells using adenoviral vectors. Comparative study of the activities of three representative ubiquitously active promoters revealed that only the CA promoter allowed robust transgene expression in human pluripotent stem cells. In addition, we established a protocol that allowed us to efficiently introduce target genes and ensure their expression even in small numbers of cells. Adenoviral vector infection of pluripotent stem cells in single-cell suspension culture yielded high gene transfer efficiency with low cytotoxicity, without losing the undifferentiated state of the pluripotent stem cells. This optimized system will facilitate developmental biology research and regenerative medicine using pluripotent stem cells. DOI： 10.1016/j.bbrc.2021.01.009 Scopus PubMed

• 1型糖尿病の残存β細胞を保護・増殖するin vivo遺伝子治療の開発2023 · 担当区分： 研究代表者 資金種別： 競争的資金 配分額： 4680000円 （ 直接経費： 3600000円 、 間接経費： 1080000円 ）
• 日本糖尿病協会インスリンメンター2015 · 日本糖尿病協会 2015年
• 浸潤・転移の骨軟部肉腫を治療可能な革新的な腫瘍溶解性ウイルス・免疫治療法の創出2000 · 配分額： 18720000円 （ 直接経費： 14400000円 、 間接経費： 4320000円 ）
• 免疫チェックポイントBispecific抗体遺伝子発現・腫瘍溶解性ウイルスの創出2000 · 配分額： 26000000円 （ 直接経費： 20000000円 、 間接経費： 6000000円 ）

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