Development of novel multi-target drugs for intractable amyloidoses

• Project/Area Number: 15K15006
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: Jono Hirofumi 熊本大学, 医学部附属病院, 准教授 (40515483)
• Co-Investigator(Kenkyū-buntansha): 安東 由喜雄 熊本大学, 大学院生命科学研究部(医), 教授 (20253742) ; 有馬 英俊 熊本大学, 大学院生命科学研究部(薬), 教授 (50260964) ; 白木 伸明 東京工業大学, 生命理工学院, 准教授 (70448520)
• Research Collaborator: Butler James
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 高機能性遺伝子キャリア / アミロイドーシス / 家族性アミロイドポリニューロパチー

Outline of Final Research Achievements

Intractable amyloidoses progress through 3 critical pathological processes, 1. Overproduction or mutation of amyloid precursor proteins, 2. Amyloid fibril formation caused by conformational change, 3. Tissue deposition of amyloid fibrils. However, as of this moment, no clinically effective therapy targeting each pathological process independently is available. In this research, we utilized characteristic features of polyamidoamine starburst dendrimer as a multifunctional material and developed novel multi-target drugs (GUG-β-CDE) for FAP effectively suppressing 3 pathological process in parallel.

Research Products

• [Int'l Joint Research] Alnylam Pharmaceuticals, Inc.(米国)
• [Journal Article] Novel Antibody for the Treatment of Transthyretin Amyloidosis. (2016)
  • Author(s): Hosoi A, Su Y, Torikai M, Jono H, Ishikawa D, Soejima K, Higuchi H, Guo J, Ueda M, Suenaga G, Motokawa H, Ikeda T, Senju S, Nakashima T, Ando Y
  • Journal Title: J Biol Chem Volume: 291 Pages: 25096-25105
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Sources of variation of transthyretin in healthy subjects in East and Southeast Asia: Clinical and experimental evidence for the effect of alcohol on transthyretin metabolism. (2016)
  • Author(s): Jono H, Su Y, Obayashi K, Tanaka Y, Ishiguro A, Nishimura H, Shinriki S, Ueda M, Ikeda K, Yamagata K, Ichihara K, Ando Y; Scientific Committee for the Asia-Pacific Federation of Clinical Biochemistry.
  • Journal Title: Clin Chim Acta Volume: 458 Pages: 240-5
  • DOI: 10.1016/j.cca.2016.04.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-term outcome of patients with hereditary transthyretin V30M amyloidosis with Polyneuropathy after liver transplantation (2016)
  • Author(s): Okumura K, Yamashita T, Masuda T, Misumi Y, Ueda A, Ueda M, Obayashi K, Jono H, Yamashita S, Inomata Y, Ando Y
  • Journal Title: Amyloid Volume: 13 Pages: 1-7
  • Peer Reviewed
• [Journal Article] Long-term outcome of patients with hereditary transthyretin V30M amyloidosis with polyneuropathy after liver transplantation. (2016)
  • Author(s): Okumura K, Yamashita T, Masuda T, Misumi Y, Ueda A, Ueda M, Obayashi K, Jono H, Yamashita S, Inomata Y, Ando Y.
  • Journal Title: Amyloid Volume: 23 Issue: 1 Pages: 39-45
  • DOI: 10.3109/13506129.2015.1123149
  • Peer Reviewed
• [Journal Article] Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis. (2015)
  • Author(s): Yanagisawa A, Ueda M, Sueyoshi T, Okada T, Fujimoto T, Ogi Y, Kitagawa K, Tasaki M, Misumi Y, Oshima T, Jono H, Obayashi K, Hirakawa K, Uchida H, Westermark P, Ando Y, Mizuta H.
  • Journal Title: Mod Pathol Volume: 28 Issue: 2 Pages: 201-207
  • DOI: 10.1038/modpathol.2014.102
  • Peer Reviewed
• [Journal Article] Inhibition of insulin amyloid fibril formation by cyclodextrins. (2015)
  • Author(s): Kitagawa K, Misumi Y, Ueda M, Hayashi Y, Tasaki M, Obayashi K, Yamashita T, Jono H, Arima H, Ando Y.
  • Journal Title: Amyloid Volume: 22 Issue: 3 Pages: 181-186
  • DOI: 10.3109/13506129.2015.1064818
  • Peer Reviewed
• [Presentation] 質量分析法が変える難治性アミロイドーシスの治療戦略 (2017)
  • Author(s): 城野博史、田崎雅義、安東由喜雄
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-24
  • Invited
• [Presentation] 家族性アミロイドポリニューロパチー患者由来iPS細胞を用いた病態解および創薬スクリーニングの有用性 (2016)
  • Author(s): 城野博史、竹下うらん、大内健太、成田泰子、磯野香織、大矢雄希、猪股裕紀洋、安東由喜雄
  • Organizer: 第56回日本臨床化学会年次学術集会
  • Place of Presentation: 熊本
  • Year and Date: 2016-12-02
• [Presentation] アミロイドーシス根治を目指した革新的マルチターゲット型治療薬の創製 (2016)
  • Author(s): 城野博史
  • Organizer: 第4回TR推進合同フォーラム・ライフサイエンス技術交流会
  • Place of Presentation: 福岡
  • Year and Date: 2016-10-31
• [Presentation] Therapeutic effect of polyamidoamine dendrimer on transthyretin-related amyloidosis (2016)
  • Author(s): Jono H, Anno T, Hayashi Y, Motoyama K, Ueda M, Obayashi K, Arima H, Ando Y
  • Organizer: XV International Symposium on Amyloidosis
  • Place of Presentation: Uppsala, Sweden
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] アミロイドーシス根治を目指した革新的マルチターゲット型治療薬の創製 (2015)
  • Author(s): 城野博史
  • Organizer: 第3回TR推進合同フォーラム
  • Place of Presentation: 福岡
  • Year and Date: 2015-08-31
• [Presentation] Novel cyclodextrin-based therapeutic approaches for refractory Amyloidosis (2015)
  • Author(s): Jono H, Inoue M, Fujisawa K, Hayashi Y, Anno T, Motoyama K, Ando Y, Arima H
  • Organizer: 8th Asian Cyclodextrin Conference and 32nd Cyclodextrin Symposium
  • Place of Presentation: Kumamoto
  • Year and Date: 2015-05-14
  • Int'l Joint Research / Invited
• [Patent(Industrial Property Rights)] 新規なアミロイド線維生成抑制剤 (2016)
  • Inventor(s): 城野博史、有馬英俊、安東由喜雄、本山敬一、東大志
  • Industrial Property Rights Holder: 城野博史、有馬英俊、安東由喜雄、本山敬一、東大志
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-06-10
• [Patent(Industrial Property Rights)] 新規なアミロイド線維生成抑制剤 (2015)
  • Inventor(s): 城野博史、有馬英俊、安東由喜雄、本山敬一、東大志
  • Industrial Property Rights Holder: 城野博史、有馬英俊、安東由喜雄、本山敬一、東大志
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-117150
  • Filing Date: 2015-06-10