TTC39B標的RNA医薬搭載肝特異的バイオナノカプセルによる脂肪肝炎治療薬開発

2020 Fiscal Year Annual Research Report

• Project/Area Number: 18H03532
• Research Institution: Osaka University
• Principal Investigator: 小関 正博 大阪大学, 医学系研究科, 助教 (10467582)
• Co-Investigator(Kenkyū-buntansha): 黒田 俊一 大阪大学, 産業科学研究所, 教授 (60263406)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 核酸医薬 / PCSK9 / バイオナノカプセル / 脂肪肝炎 / 肝特異的 / 肥満マウス / ７ケトコレステロール

Outline of Annual Research Achievements

申請者は、endonuclease耐性が高くなる独自のたんぱく修飾をした核酸作成技術をもつA社と共同研究契約を結び、LDL受容体の発現調節に関与しているPCSK9に対して、マウスのヒトで保存されている配列を選択しRNAiを作成した。前年度に引き続き、Hepa1-6などの細胞株にて、ナノキャリアとRNAiの配合条件の最適化を行った。野生型C57Bl/6マウスに対する投与実験では、一部興味深いデータが得られたが、粒子のサイズの不均一に起因すると思われる塞栓症を来すことがあり、引き続き条件の最適化を行っている。
一方、ライフスタイルに起因した新しい脂肪肝炎の作成に取り組み、食事性酸化コレステロールである、7-ketocholesterol（7KC）に着目し、7KCが、肥満/糖尿病モデルマウスで、ミトコンドリア活性の低下、オートファジーメカニズムの変調、炎症性サイトカインの発現増加を介して、脂肪蓄積、炎症細胞浸潤を増悪し、脂肪肝炎を増悪させることを見出し、論文化した（Frontier in Endocrinology 2020）。本脂肪肝炎モデルは、これまでのメチオニン・コリン欠乏食負荷（MCD）による脂肪肝炎と比較して、よりヒトの脂肪肝炎の組織像に近い所見がえられており、今後の核酸医薬の試験に有用であると考えられる。
その他、日本動脈硬化学会作成の動脈硬化性疾患予防ガイドライン2022年版に非アルコール性脂肪性肝疾患と心血管疾患を追加することを検討することになり、システマティックレビューを行った。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Dietary Oxysterol, 7-Ketocholesterol Accelerates Hepatic Lipid Accumulation and Macrophage Infiltration in Obese Mice (2021)
  • Author(s): Chang Jiuyang、Koseki Masahiro、Saga Ayami、Kanno Kotaro、Higo Tomoaki、Okuzaki Daisuke、Okada Takeshi、Inui Hiroyasu、Tanaka Katsunao、Asaji Masumi、Zhu Yinghong、Kamada Yoshihiro、Ono Masafumi、Saibara Toshiji、Ichi Ikuyo、Ohama Tohru、Nishida Makoto、Yamashita Shizuya、Sakata Yasushi
  • Journal Title: Frontiers in Endocrinology Volume: 11 Pages: 1-11
  • DOI: 10.3389/fendo.2020.614692
  • Peer Reviewed / Open Access
• [Journal Article] FIB-4 First in the Diagnostic Algorithm of Metabolic-Dysfunction-Associated Fatty Liver Disease in the Era of the Global Metabodemic (2021)
  • Author(s): Sumida Yoshio、Yoneda Masashi、Tokushige Katsutoshi、Kawanaka Miwa、Fujii Hideki、Yoneda Masato、Imajo Kento、Takahashi Hirokazu、Eguchi Yuichiro、Koseki Masahiro、Yoshida Yuichi、Kawaguchi Takumi、Kamada Yoshihiro、Okanoue Takeshi、Nakajima Atsushi、Japan Study Group of NAFLD
  • Journal Title: Life Volume: 11 Pages: 143～143
  • DOI: 10.3390/life11020143
  • Peer Reviewed / Open Access
• [Journal Article] A Resuscitated Case of Acute Myocardial Infarction with both Familial Hypercholesterolemia Phenotype Caused by Possibly Oligogenic Variants of the <i>PCSK9</i> and <i>ABCG5</i> Genes and Type I CD36 Deficiency (2021)
  • Author(s): Nishikawa Ryo、Furuhashi Masato、Hori Mika、Ogura Masatsune、Harada-Shiba Mariko、Okada Takeshi、Koseki Masahiro、Kujiraoka Takeshi、Hattori Hiroaki、Ito Ryosuke、Muranaka Atsuko、Kokubu Nobuaki、Miura Tetsuji
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Pages: -
  • DOI: 10.5551/jat.58909
  • Peer Reviewed / Open Access
• [Journal Article] Marked effects of novel selective peroxisome proliferator-activated receptor α modulator, pemafibrate in severe hypertriglyceridemia: preliminary report (2020)
  • Author(s): Iitake Chie、Masuda Daisaku、Koseki Masahiro、Yamashita Shizuya
  • Journal Title: Cardiovascular Diabetology Volume: 19 Pages: 201-206
  • DOI: 10.1186/s12933-020-01172-8
  • Peer Reviewed / Open Access
• [Journal Article] Development and Clinical Application of an Enzyme-Linked Immunosorbent Assay for Oxidized High-Density Lipoprotein (2020)
  • Author(s): Okada Takeshi、Sumida Mizuki、Ohama Tohru、Katayama Yuki、Saga Ayami、Inui Hiroyasu、Kanno Kotaro、Masuda Daisaku、Koseki Masahiro、Nishida Makoto、Sakata Yasushi、Yamashita Shizuya
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 27 Pages: -
  • DOI: 10.5551/jat.56887
  • Peer Reviewed / Open Access
• [Journal Article] Progesterone receptor membrane associated component 1 enhances obesity progression in mice by facilitating lipid accumulation in adipocytes (2020)
  • Author(s): Furuhata Ryogo、Kabe Yasuaki、Kanai Ayaka、Sugiura Yuki、Tsugawa Hitoshi、Sugiyama Eiji、Hirai Miwa、Yamamoto Takehiro、Koike Ikko、Yoshikawa Noritada、Tanaka Hirotoshi、Koseki Masahiro、Nakae Jun、Matsumoto Morio、Nakamura Masaya、Suematsu Makoto
  • Journal Title: Communications Biology Volume: 3 Pages: 479-492
  • DOI: 10.1038/s42003-020-01202-x
  • Peer Reviewed / Open Access
• [Journal Article] Evinacumab for Homozygous Familial Hypercholesterolemia (2020)
  • Author(s): Raal Frederick J.、Rosenson Robert S.、Reeskamp Laurens F.、Hovingh G. Kees、Kastelein John J.P.、Rubba Paolo、Ali Shazia、Banerjee Poulabi、Chan Kuo-Chen、Gipe Daniel A.、Khilla Nagwa、Pordy Robert、Weinreich David M.、Yancopoulos George D.、Zhang Yi、Gaudet Daniel
  • Journal Title: New England Journal of Medicine Volume: 383 Pages: 711～720
  • DOI: 10.1056/NEJMoa2004215
  • Peer Reviewed / Open Access
• [Journal Article] Serum Mac-2 Binding Protein Levels Associate with Metabolic Parameters and Predict Liver Fibrosis Progression in Subjects with Fatty Liver Disease: A 7-Year Longitudinal Study (2020)
  • Author(s): Kamada Yoshihiro、Morishita Koichi、Koseki Masahiro、Nishida Mayu、Asuka Tatsuya、Naito Yukiko、Yamada Makoto、Takamatsu Shinji、Sakata Yasushi、Takehara Tetsuo、Miyoshi Eiji
  • Journal Title: Nutrients Volume: 12 Pages: 1770～1770
  • DOI: 10.3390/nu12061770
  • Peer Reviewed / Open Access
• [Journal Article] Loss of core fucosylation reduces low-density lipoprotein receptor expression in hepatocytes by inducing PCSK9 production (2020)
  • Author(s): Kamada Yoshihiro、Yamamoto Akiko、Fujiyoshi Anna、Koseki Masahiro、Morishita Koichi、Asuka Tatsuya、Takamatsu Shinji、Sakata Yasushi、Takehara Tetsuo、Taniguchi Naoyuki、Miyoshi Eiji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 527 Pages: 682～688
  • DOI: 10.1016/j.bbrc.2020.05.019
  • Peer Reviewed / Open Access
• [Journal Article] Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis (2020)
  • Author(s): Sumida Yoshio、Yoneda Masashi、Tokushige Katsutoshi、Kawanaka Miwa、Fujii Hideki、Yoneda Masato、Imajo Kento、Takahashi Hirokazu、Eguchi Yuichiro、Koseki Masahiro、Yoshida Yuichi、Kawaguchi Takumi、Kamada Yoshihiro、Okanoue Takeshi、Nakajima Atsushi、Japan Study Group of NAFLD
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Pages: 1907～1907
  • DOI: 10.3390/ijms21061907
  • Peer Reviewed / Open Access
• [Presentation] Cardiac inflammation and dysfunction were accompanied with cholesterol-dominant steatohepatitis induced by atherogenic-diet (2021)
  • Author(s): Kanno K, Koseki M, Sakata Y
  • Organizer: Cardiovascular and Metabolic Week 2020
  • Int'l Joint Research
• [Presentation] High Fat Diet Containing 7-Ketocholesterol Induces Steatohepatitis and Cardiac Inflammation in STZ-Induced Diabetic Mice (2021)
  • Author(s): Masahiro Koseki、Juyang Chang、Kotaro Kanno、Ayami Saga、Hiroyasu Inui、Takeshi Okada、Shigeyoshi Saito、Tomoaki Higo、Seiko Ide、Katsunao Tanaka、Yinghong Zhu、Toru Ohhama、Makoto Nishida、Shizuya Yamashita、Yasushi Sakata
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Progranulin Deficiency Leads to Enhanced Age-related Cardiac Hypertrophy through Complement C1q-induced Beta-catenin Activation (2021)
  • Author(s): Yinghong Zhu、Toru Ohama、Katsunao Tanaka、Kotaro Kanno、Jiuyang Chang、Hiroyasu Inui、Takeshi Okada、Masahiro Koseki、Makoto Nishida、Shizuya Yamashita、Yasushi Sakata
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] A dietary oxysterol, 7-ketocholesterol, exacerbates imiquimod-induced psoriasis-like dermatitis in steatohepatitis mice (2020)
  • Author(s): Saga A, Koseki M, Kanno K, Chang J, Asaji M, Okada T, Inui H, Zhu Y, Ohama T, Nishida M, Yamashita S, Sakata Y
  • Organizer: 日本研究皮膚科学会 第45回年次学術大会・総会
• [Presentation] Pemafibrate Suppresses Liver Inflammation Caused by Atherogenic Diet and Improves Cardiac Function. (2020)
  • Author(s): Kanno K, Koseki M, Saga A, Chang J, Okada T, Inui H, Asaji M, Zhu Y, Ohama T, Nishida M, Yamashita S, Sakata Y
  • Organizer: American Heart Association Scientific Sessions 2020
  • Int'l Joint Research
• [Presentation] Targeted Exon Sequencing of Lipid-Related Genes in Patients with Clinically Diagnosed Familial Hypercholesterolemia (2020)
  • Author(s): Okada T, Koseki M, Nishida M, Tanaka K, Inui H, Kanno K, Saga A, Ohama T, Kujiraoka T, Hattori H, Yamashita S, Sakata Y
  • Organizer: American Heart Association Scientific Sessions 2020
  • Int'l Joint Research
• [Presentation] Immunometabolic Disorder in Cardiovascular System and Liver Mediated by Long-term Exposure to Dietderived Oxidized Cholesterol, 7-Ketocholesterol (2020)
  • Author(s): Koseki M, Kanno K, Saga A, Chang J, Inui H, Okada T, Ohama T, Nishida M, Kamada Y, Miyoshi E, Yamashita S, Sakata Y
  • Organizer: Y 88th European Atherosclerosis Congress (EAS)
  • Int'l Joint Research
• [Presentation] Prevalence of Coronary Artery Disease and Achievement of Low-density Lipoprotein Cholesterol Management Targets in Familial Hypercholesterolemia Patients at Osaka University Hospital (2020)
  • Author(s): Okada T, Koseki M, Inui H, Kanno K, Saga A, Ohama T, Nishida M, Yamashita S, Sakata Y
  • Organizer: 88th European Atherosclerosis Congress (EAS)
  • Int'l Joint Research
• [Presentation] A Selective PPARα Modulator, Pemafibrate Reduced Hepatic Fibrosis and Cardiac Inflammation in Cholesterol-Dominant, Atherogenic-Diet Induced Steatohepatitis Model in STZ Induced Diabetic Mice. (2020)
  • Author(s): Chang J, Koseki M, Saga A, Kanno K, Okada T, Saito S, Kamada Y, Inui H, Asaji M, Zhu Y, Ohama T, Nishida M, Yamashita S, Sakata Y
  • Organizer: 第4回日本循環器学会基礎研究フォーラム（BCVR）
• [Presentation] Pemafibrate Improves Steatohepatitis and Cardiac Function in Atherogenic-diet Mice Model (2020)
  • Author(s): Kanno K, Koseki M, Saga A, Chang J, Okada T, Tanaka K, Inui H, Asaji M, Zhu Y, Ohama T, Nishida M, Yamashita S, Sakata Y
  • Organizer: 第4回日本循環器学会基礎研究フォーラム（BCVR）
• [Presentation] 食餌誘導性肝線維化モデルにおけるペマフィブラートの肝臓、心臓への作用メカニズムの解明 (2020)
  • Author(s): 小関正博, 冠野昂太郎, 常久洋, 嵯峨礼美, 岡田健志, 乾洋勉, 齋藤茂芳, 鎌田佳宏, 山下静也, 坂田泰史
  • Organizer: 第56回日本肝臓学会総会
  • Invited
• [Presentation] 食事由来酸化ステロール蓄積のNAFLD、動脈硬化の進展における影響 (2020)
  • Author(s): 小関正博, 三善英知, 西原利治
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] The dietary 7-Ketocholesterol accelerated steatohepatitis in ob/ob mice by suppressing autophagy (2020)
  • Author(s): 常久洋, Koseki M, 嵯峨礼美
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] イミキモド誘導乾癬モデルマウスにおける食事誘導脂肪肝炎の影響 (2020)
  • Author(s): 嵯峨礼美, 常久洋, 小関正博
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] The Role of Th1 and Th17 During Myocardial Infarction and Inhibitory Effect of Probucol on Th1 in SR-BI KO/ApoeR61h/h Mice (2020)
  • Author(s): Inui H, Nishida M, Asaji M, Saga A, Kanno K, Okada T, Koseki M, Chang J, Zhu Y, Ohama T, Yamashita S, Sakata Y
  • Organizer: 第84回日本循環器学会学術集会
• [Presentation] A selective PPARα modulator, pemafibrate reduced hepatic cholesterol accumulation and inflammatory cell infiltration in atherogenic-diet induced steatohepatitis mouse model (2020)
  • Author(s): 冠野昂太郎, 小関正博, 嵯峨礼美, 常久洋, 岡田健志, 乾洋勉, 朝治真澄, 朱穎竑, 大濱透, 西田誠, 山下静也, 坂田泰史
  • Organizer: 第84回日本循環器学会学術集会
• [Presentation] The Current Status of Achievement of Low-density Lipoprotein Cholesterol Management Targets in Familial Hypercholesterolemia Patients in Osaka University Hospital (2020)
  • Author(s): Okada T, Koseki M, Inui H, Kanno K, Chang J, Zhu Y, Saga A, Asaji M, Ohama T, Nishida M, Yamashita S, Sakata Y
  • Organizer: 第84回日本循環器学会学術集会
• [Presentation] 動脈硬化惹起食誘導脂肪肝炎モデルにおける、ペマフィブラートの抗脂肪肝炎、抗心筋炎症作用の解明 (2020)
  • Author(s): 小関正博、冠野昂太郎、常久洋、嵯峨礼美、岡田健志、鎌田佳宏、山下静也、坂田泰史
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] NAFLD/NASH、動脈硬化進展における外因性酸化ステロール7-ketocholesterolの影響 (2020)
  • Author(s): 小関正博, 冠野昂太郎, 常久洋, 嵯峨礼美, 岡田健志, 乾洋勉, 鎌田佳宏, 山下静也, 坂田泰史
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] 食餌誘発性脂肪肝炎マウスモデルにおいて7-ketocholesterolはイミキモド誘導乾癬様皮膚炎を増悪させる (2020)
  • Author(s): 嵯峨礼美, 小関正博, 冠野昂太郎, 常久洋, 朝治真澄, 岡田健志, 鎌田佳宏, 乾洋勉, 朱穎竑, 大濵透, 西田誠, 山下静也, 坂田泰史
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
• [Presentation] The Dietary 7-ketocholesterol Accelerated Steatohepatitis in STZ Induced Diabetic Mice (2020)
  • Author(s): Chang J, Koseki M, Saga A, Kanno K, Okada T, Saito S, Kamada Y, Inui H, Asaji M, Zhu Y, Ohama T, Nishida M, Yamashita S, Sakata Y
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
• [Presentation] Progranulin deficiency leads to enhanced age-related cardiac hypertrophy through Clq-induced β-catenin activation (2020)
  • Author(s): 朱穎竑, 大濵透, 常久洋, 乾洋勉, 冠野昂太郎, 岡田健志, 小関正博, 西田誠, 坂田泰史, 山下静也
  • Organizer: 第52回日本動脈硬化学会総会・学術集会