Development of Hydrodynamics-based Gene Therapy for the Pancreatic Cancer

• Project/Area Number: 20K08379
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Niigata University
• Principal Investigator: 上村 顕也 新潟大学, 医歯学系, 特任教授 (00579146)
• Co-Investigator(Kenkyū-buntansha): 寺井 崇二 新潟大学, 医歯学系, 教授 (00332809) ; 坂牧 僚 新潟大学, 医歯学系, 助教 (40792289) ; 横尾 健 新潟大学, 医歯学総合研究科, 特任准教授 (80750629)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Discontinued (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 遺伝子治療 / ハイドロダイナミック遺伝子導入法 / 膵臓癌 / 膵癌遺伝子治療 / 核酸医薬 / 膵癌

Outline of Research at the Start

本研究では、膵癌に対する新規治療法として、臓器選択的なハイドロダイナミック遺伝子導入法による遺伝子治療が応用可能か、検討することを目的とする。その目的を達成するために、膵癌モデル動物の確立、膵癌遺伝子治療のための治療遺伝子の選択、抗腫瘍効果、安全性を評価する。申請者らがこれまでに報告した、臓器選択的な遺伝子導入及びそのシステムを使用して、これまでに確立した治療遺伝子を応用する点でも実現性の高い、創造的な研究であると考える。

Outline of Annual Research Achievements

膵癌は、手術以外の有効な治療法がなく、化学療法の効果も十分でないことから、わが国の癌死の第4位を占め、増加傾向にある予後不良な疾患である。従って、基礎研究の成果に基づく、新規治療法の開発が喫緊の課題である。5年生存率が10%以下という、疾患の進行速度を考慮すると、少ない治療回数で、より長期間の治療効果を示す新規治療法のニーズが高く、その点で遺伝子治療の特徴、利点が合致すると考えた。
そこで本課題では、膵臓に対して臓器選択的HGDを確立し、膵癌の遺伝子治療法に応用するための方法論を学術的に検証することを目的として研究を行った。
令和２、３年度に癌関連遺伝子発現プラスミドDNAを膵臓選択的に導入し、効率的に膵癌モデルを作製するためのHGDパラメータを確立した。具体的には、各種の膵癌関連遺伝子発現ベクター(MYC, KRAS及びその変異体KRASG12D, NRAS及びYAP遺伝子)またその組み合わせの遺伝子溶液を野生型ラットの膵臓選択的にHGDした。導入核酸量、注入速度、溶液量などのHGDパラメータと導入後経過時間、発癌遺伝子の組み合わせを行った。その結果、膵管上皮の異型から癌病変である膵上皮内腫瘍性病変を形成する素地となる腺房-導管異形成の発生や悪性度の高い膵癌、肝臓、皮下、リンパ節転移モデルまで様々な段階の膵癌モデルを作成することができた(特許第6943427号)（特願2020-102959）(論文　Cancers 2020; Mol. Ther. Nucleic. Acids 2022)。
そこで、令和４年度には、膵癌細胞で上皮系マーカーであるEカドヘリンの発現低下と、間葉系マーカーであるNカドヘリンの発現上昇を認めるなど、この膵癌モデルの癌組織及び周辺組織の遺伝子発現変化の検討から、膵癌遺伝子治療のための細胞選択性を担保するためのプロモーター候補が選択された(論文投稿中)。以上の結果から、膵臓選択的なHGDが膵癌治療に有用な方法論として応用できることが明らかとなった。

Research Products

• [Journal Article] Effects of Atezolizumab and Bevacizumab on Adrenal Gland Metastasis of Hepatocellular Carcinoma: A Case Report and Review of Literature (2022)
  • Author(s): Ishikawa Natsuki、Kamimura Kenya、Endo Saori、Ishii Soichi、Ogawa Kazuya、Sakai Norihiro、Abe Hiroyuki、Ko Masayoshi、Shibata Osamu、Koseki Youhei、Yokoyama Junji、Sakamaki Akira、Terai Shuji
  • Journal Title: Internal Medicine Volume: 61 Issue: 21 Pages: 3233-3237
  • DOI: 10.2169/internalmedicine.9341-22
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-11-01
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a pancreatic cancer animal model using the pancreas-targeted hydrodynamic gene delivery method (2022)
  • Author(s): Shibata Osamu、Kamimura Kenya、Tanaka Yuto、Ogawa Kohei、Owaki Takashi、Oda Chiyumi、Morita Shinichi、Kimura Atsushi、Abe Hiroyuki、Ikarashi Satoshi、Hayashi Kazunao、Yokoo Takeshi、Terai Shuji
  • Journal Title: Molecular Therapy - Nucleic Acids Volume: 28 Pages: 342-352
  • DOI: 10.1016/j.omtn.2022.03.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Longitudinal increase in albumin?bilirubin score is associated with non-malignancy-related mortality and quality of life in patients with liver cirrhosis (2022)
  • Author(s): Sakamaki A, Takamura M, Sakai N, Watanabe Y, Arao Y, Kimura N, Setsu T, Abe H, Yokoo T, Kamimura H, Tsubata S, Waguri N, Ishikawa T, Kawai H, Sugitani S, Sato T, Funakoshi K, Watanabe M, Igarashi K, Kamimura K, et al.
  • Journal Title: PLOS ONE Volume: 17 Issue: 2 Pages: e0263464-e0263464
  • DOI: 10.1371/journal.pone.0263464
  • Peer Reviewed / Open Access
• [Journal Article] Effects of a novel selective PPARα modulator, statin, sodium-glucose cotransporter 2 inhibitor, and combinatorial therapy on the liver and vasculature of medaka nonalcoholic steatohepatitis model (2022)
  • Author(s): Kimura Atsushi、Kamimura Kenya、Ohkoshi-Yamada Marina、Shinagawa-Kobayashi Yoko、Goto Ryo、Owaki Takashi、Oda Chiyumi、Shibata Osamu、Morita Shinichi、Sakai Norihiro、Abe Hiroyuki、Yokoo Takeshi、Sakamaki Akira、Kamimura Hiroteru、Terai Shuji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 596 Pages: 76-82
  • DOI: 10.1016/j.bbrc.2022.01.086
  • Peer Reviewed
• [Journal Article] Involvement of the liver-gut peripheral neural axis in nonalcoholic fatty liver disease pathologies via hepatic HTR2A (2022)
  • Author(s): Owaki Takashi、Kamimura Kenya、Ko Masayoshi、Nagayama Itsuo、Nagoya Takuro、Shibata Osamu、Oda Chiyumi、Morita Shinichi、Kimura Atsushi、Sato Takeki、Setsu Toru、Sakamaki Akira、Kamimura Hiroteru、Yokoo Takeshi、Terai Shuji
  • Journal Title: Disease Models & Mechanisms Volume: 15 Issue: 7
  • DOI: 10.1242/dmm.049612
  • Peer Reviewed
• [Journal Article] Effects of a selective PPARα modulator, sodium-glucose cotransporter 2 inhibitor, and statin on the myocardial morphology of medaka nonalcoholic fatty liver disease model (2022)
  • Author(s): Ohkoshi-Yamada Marina、Kamimura Kenya、Kimura Atsushi、Tanaka Yuto、Nagayama Itsuo、Yakubo Shunta、Abe Hiroyuki、Yokoo Takeshi、Sakamaki Akira、Kamimura Hiroteru、Terai Shuji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 625 Pages: 116-121
  • DOI: 10.1016/j.bbrc.2022.07.117
  • Peer Reviewed
• [Journal Article] Cyclin D1 Binding Protein 1 Responds to DNA Damage through the ATM / CHK2 Pathway (2022)
  • Author(s): Niwa Yusuke、Kamimura Kenya、Ogawa K、Oda C、Tanaka Y、Horigome R、Ohtsuka M、Miura H、Fujisawa Koichi、Yamamoto Naoki、Takami Taro、Okuda Shujiro、Ko Masayoshi、Owaki Takashi、Kimura Atsushi、Shibata Osamu、Morita Shinichi、Sakai N、Abe H、Yokoo T、Sakamaki A、Kamimura H、Terai S
  • Journal Title: Journal of Clinical Medicine Volume: 11 Issue: 3 Pages: 851-851
  • DOI: 10.3390/jcm11030851
  • Peer Reviewed / Open Access
• [Journal Article] Use of a Deep Learning Approach for the Sensitive Prediction of Hepatitis B Surface Antigen Levels in Inactive Carrier Patients (2022)
  • Author(s): Kamimura Hiroteru、Nonaka Hirofumi、Mori Masaya、Kobayashi Taichi、Setsu Toru、Kamimura Kenya、Tsuchiya Atsunori、Terai Shuji
  • Journal Title: Journal of Clinical Medicine Volume: 11 Issue: 2 Pages: 387-387
  • DOI: 10.3390/jcm11020387
  • Peer Reviewed
• [Journal Article] Intestinal duplication diagnosed preoperatively with double-balloon enteroscopy: an extremely rare case report and literature review (2022)
  • Author(s): Niwa Yusuke、Tominaga Kentaro、Kawata Yuzo、Kobayashi Takamasa、Mizuwasa Takeshi、Takahashi Kazuya、Sato Hiroki、Kohisa Junji、Abe Satoshi、Kamimura Kenya、Yokoyama Junji、Kawai Hirokazu、Sugino Hideaki、Umezu Hajime、Hirai Yumiko、Nakano Masato、Shimada Yoshifumi、Kameyama Hitoshi、Wakai Toshifumi、Terai Shuji
  • Journal Title: Clinical Journal of Gastroenterology Volume: 15 Issue: 2 Pages: 381-387
  • DOI: 10.1007/s12328-022-01596-7
  • Peer Reviewed
• [Journal Article] Hydrogen-producing small intestinal bacterial overgrowth is associated with hepatic encephalopathy and liver function (2022)
  • Author(s): Yokoyama Kunihiko、Sakamaki Akira、Takahashi Kazuya、Naruse Takumi、Sato Chihiro、Kawata Yuzo、Tominaga Kentaro、Abe Hiroyuki、Sato Hiroki、Tsuchiya Atsunori、Kamimura Kenya、Takamura Masaaki、Yokoyama Junji、Terai Shuji
  • Journal Title: PLOS ONE Volume: 17 Issue: 2 Pages: e0264459-e0264459
  • DOI: 10.1371/journal.pone.0264459
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Lenvatinib on a Hepatocellular Carcinoma with Fibroblast Growth Factor Receptor 4 Expression: A Case Report and Review of the Literature (2021)
  • Author(s): Shibata Osamu、Kamimura Kenya、Ko Masayoshi、Sakai Norihiro、Abe Hiroyuki、Morita Shinichi、Mizusawa Takeshi、Sato Hiroki、Sakamaki Akira、Terai Shuji
  • Journal Title: Internal Medicine Volume: 60 Issue: 11 Pages: 1709-1715
  • DOI: 10.2169/internalmedicine.6580-20
  • NAID: 130008046766
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-06-01
  • Peer Reviewed
• [Journal Article] Multiple Tumor-Like Fatty Changes in the Liver Disappeared After Hepatitis C Virus Eradication With Direct-Acting Antiviral Treatment (2021)
  • Author(s): Sakai Norihiro、Kamimura Kenya、Terai Shuji
  • Journal Title: American Journal of Gastroenterology Volume: 116 Issue: 2 Pages: 237-237
  • DOI: 10.14309/ajg.0000000000000703
  • Peer Reviewed
• [Journal Article] Relationship between detection of hepatitis B virus in saliva and periodontal disease in hepatitis B virus carriers in Japan， Journal of Infection and Chemotherapy (2021)
  • Author(s): Kamimura Hiroteru, Jun Watanabe, Tomoyuki Sugano, Junji Kohisa, Hiroyuki Abe, Keny Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Shogo Okoshi, Yoshinari Tanabe, Ritsuo Takagi, Hirofumi Nonaka, Shuji Terai
  • Journal Title: Journal of Infection and Chemotherapy Volume: Vol.27, No.3 Issue: 3 Pages: 492-496
  • DOI: 10.1016/j.jiac.2020.10.028
  • Peer Reviewed / Open Access
• [Journal Article] Adipose most abundant 2 protein is a predictive marker for cisplatin sensitivity in cancers (2021)
  • Author(s): Kamimura Kenya、Suda Takeshi、Fukuhara Yasuo、Okuda Shujiro、Watanabe Yu、Yokoo Takeshi、Osaki Akihiko、Waguri Nobuo、Ishikawa Toru、Sato Toshihiro、Aoyagi Yutaka、Takamura Masaaki、Wakai Toshifumi、Terai Shuji
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 6255-6255
  • DOI: 10.1038/s41598-021-85498-7
  • Peer Reviewed
• [Journal Article] Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver (2021)
  • Author(s): Ko Masayoshi、Kamimura Kenya、Owaki Takashi、Nagoya Takuro、Sakai Norihiro、Nagayama Itsuo、Niwa Yusuke、Shibata Osamu、Oda Chiyumi、Morita Shinichi、Kimura Atsushi、Inoue Ryosuke、Setsu Toru、Sakamaki Akira、Yokoo Takeshi、Terai Shuji
  • Journal Title: Disease Models & Mechanisms Volume: 14 Issue: 3
  • DOI: 10.1242/dmm.048922
  • Peer Reviewed
• [Journal Article] The promise of radiotherapy for hepatocellular carcinoma (2021)
  • Author(s): Kamimura Kenya、Terai Shuji
  • Journal Title: Hepatology Research Volume: 51 Issue: 8 Pages: 837-838
  • DOI: 10.1111/hepr.13687
  • Peer Reviewed
• [Journal Article] The prognosis and incidence of hepatic encephalopathy of patients with liver cirrhosis treated with proton pump inhibitors (2021)
  • Author(s): Sakamaki Akira、Kamimura Kenya、Yokoo Takeshi、Osaki Akihiko、Yoshikawa Seiichi、Arao Yoshihisa、Setsu Toru、Kamimura Hiroteru、Waguri Nobuo、Takeuchi Manabu、Funakoshi Kazuhiro、Terai Shuji
  • Journal Title: Medicine Volume: 100 Issue: 32 Pages: e26902-e26902
  • DOI: 10.1097/md.0000000000026902
  • Peer Reviewed
• [Journal Article] Rare complication of hepatocellular carcinoma in Wilson's disease (2021)
  • Author(s): Ohkoshi‐Yamada Marina、Kamimura Kenya、Kamimura Hiroteru、Terai Shuji
  • Journal Title: JGH Open Volume: 5 Issue: 10 Pages: 1220-1222
  • DOI: 10.1002/jgh3.12648
  • Peer Reviewed / Open Access
• [Journal Article] Rapid progression of colonic mucinous adenocarcinoma with immunosuppressive condition: A case report and review of literature (2021)
  • Author(s): Koseki Youhei、Kamimura Kenya、Tanaka Yuto、Ohkoshi-Yamada Marina、Zhou Qiliang、Matsumoto Yoshifumi、Mizusawa Takeshi、Sato Hiroki、Sakamaki Akira、Umezu Hajime、Yokoyama Junji、Terai Shuji
  • Journal Title: World Journal of Clinical Cases Volume: 9 Issue: 30 Pages: 9182-9191
  • DOI: 10.12998/wjcc.v9.i30.9182
  • Peer Reviewed
• [Journal Article] Novel Reporter Mouse Models Useful for Evaluating In Vivo Somatic Cell Gene Editing and for Optimization of Methods of Delivering Genome Editing Tools. (2021)
  • Author(s): Miura H., Imafuku J., Kurosaki A., Sato M., Ma Y., Zhang G., Mizutani A., Kamimura K., Gurumurthy CB., Liu D., Ohtsuka M.
  • Journal Title: Molecular Therapy-Nucleic Acids. Volume: 24 Pages: 325-336
  • DOI: 10.1016/j.omtn.2021.03.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ghrelin-insulin-like growth factor-1 axis is activated via autonomic neural circuits in the non-alcoholic fatty liver disease. (2020)
  • Author(s): Nagoya T, Kamimura K, Inoue R, Ko M, Owaki T, Niwa Y, Sakai N, Setsu T, Sakamaki A, Yokoo T, Kamimura H, Nakamura Y, Ueno M, Terai S.
  • Journal Title: Neurogastroenterol Motil Volume: 32 Issue: 5
  • DOI: 10.1111/nmo.13799
  • Peer Reviewed / Open Access
• [Journal Article] Prostaglandin E2 and its receptor EP2 trigger signaling that contributes to YAP-mediated cell competition. (2020)
  • Author(s): Ishihara E, Nagaoka Y, Okuno T, Kofuji S, Ishigami-Yuasa M, Kagechika H, Kamimura K, Terai S, Yokomizo T, Sugimoto Y, Fujita Y, Suzuki A, Nishina H.
  • Journal Title: Genes Cells. Volume: 25(3) Issue: 3 Pages: 197-214
  • DOI: 10.1111/gtc.12750
  • NAID: 120006873037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of Diphtheria Toxin-Based Gene Therapy for Hepatocellular Carcinoma (2020)
  • Author(s): Kamimura Kenya、Yokoo Takeshi、Abe Hiroyuki、Sakai Norihiro、Nagoya Takuro、Kobayashi Yuji、Ohtsuka Masato、Miura Hiromi、Sakamaki Akira、Kamimura Hiroteru、Miyamura Norio、Nishina Hiroshi、Terai Shuji
  • Journal Title: Cancers Volume: 12 Issue: 2 Pages: 472-472
  • DOI: 10.3390/cancers12020472
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and Safety of the Radiotherapy for Liver Cancer: Assessment of Local Controllability and Its Role in Multidisciplinary Therapy (2020)
  • Author(s): Ohkoshi-Yamada M, Kamimura K, et al.
  • Journal Title: Cancers Volume: 12 Issue: 10 Pages: 2955-2955
  • DOI: 10.3390/cancers12102955
  • Peer Reviewed / Open Access
• [Journal Article] Obesity and accumulation of subcutaneous adipose tissue are poor prognostic factors in patients with alcoholic liver cirrhosis (2020)
  • Author(s): Sakamaki Akira、Yokoyama Kunihiko、Koyama Kyutaro、Morita Shinichi、Abe Hiroyuki、Kamimura Kenya、Takamura Masaaki、Terai Shuji
  • Journal Title: PLOS ONE Volume: 15 Issue: 11 Pages: e0242582-e0242582
  • DOI: 10.1371/journal.pone.0242582
  • Peer Reviewed
• [Journal Article] Esophageal High-Resolution Manometry for Diagnosing the Severity of the Chronic Intestinal Pseudo-Obstruction: A Case Series (2020)
  • Author(s): Sato Hiroki、Kamimura Kenya、Matsui Hideaki、Owaki Takashi、Morita Shinichi、Tanaka Yuto、Ishikawa Natsuki、Shimada Yoshifumi、Yokoyama Junji、Wakai Toshifumi、Terai Shuji
  • Journal Title: Digestive Diseases and Sciences Volume: - Issue: 11 Pages: 3960-3967
  • DOI: 10.1007/s10620-020-06701-9
  • Peer Reviewed
• [Presentation] Development of Hydrodynamics-Based Gene Therapy for Liver Cancer (2021)
  • Author(s): Kenya Kamimura
  • Organizer: ASGCT 24TH ANNUAL MEETING
  • Int'l Joint Research
• [Presentation] Establishment of a Pancreatic Cancer Animal Model using the Pancreas-Targeted Hydrodynamic Gene Delivery Method (2021)
  • Author(s): Osamu Shibata, Kenya Kamimura, et al.
  • Organizer: 2021 第27回日本遺伝子治療学会
  • Int'l Joint Research
• [Presentation] Assessment of Clinical Feasibility of Image-Guided Liver Specific Hydrodynamic Gene Transfer in Non-Human Primates (2020)
  • Author(s): Kamimura K, et al.
  • Organizer: The American Society of Gene & Cell Therapy (ASGCT)
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 膵臓癌治療システム (2020)
  • Inventor(s): 上村顕也、寺井崇二
  • Industrial Property Rights Holder: 上村顕也、寺井崇二
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Acquisition Date: 2021
• [Patent(Industrial Property Rights)] 野生型ラットの膵臓へのヒト膵癌関連遺伝子の導入による膵癌モデル動物の開発と利用 (2020)
  • Inventor(s): 上村顕也、寺井崇二、柴田理、五十嵐聡
  • Industrial Property Rights Holder: 上村顕也、寺井崇二、柴田理、五十嵐聡
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020