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Deciphering the mechanism of neuropathy and development of novel therapies in familial amyloid polyneuropathy

Research Project

Project/Area Number 17K09777
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurology
Research InstitutionNagoya University

Principal Investigator

Koike Haruki  名古屋大学, 医学系研究科, 准教授 (80378174)

Co-Investigator(Kenkyū-buntansha) 飯島 正博  名古屋大学, 医学部附属病院, 特任准教授 (40437041)
川頭 祐一  名古屋大学, 医学部附属病院, 病院講師 (40569779)
勝野 雅央  名古屋大学, 医学系研究科, 教授 (50402566)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords家族性アミロイドポリニューロパチー / アミロイド / アミロイドーシス / トランスサイレチン / ニューロパチー / 家族性アミロイトポリニューロパチー
Outline of Final Research Achievements

Transthyretin (TTR) Val30Met familial amyloid polyneuropathy (FAP) (FAP ATTR Val30Met) is the most common type of FAP. Long amyloid fibers were abundant in the conventional early-onset Val30Met cases from endemic foci, whereas the amyloid fibrils were generally short in the late-onset Val30Met and non-Val30Met cases from non-endemic areas. The distortion of Schwann cells close to amyloid fibril masses was conspicuous, particularly in cases with long amyloid fibrils. Findings suggestive of the disruption of blood-nerve barriers, such as the loss of tight junctions and the fenestration of endothelial cells, were frequently found particularly in late-onset FAP cases. These findings suggest that direct insult of amyloid fibrils causes Schwann cell damage resulting in the predominant loss of small-fiber axons characteristic of early onset cases. In addition, vasculopathy may also participate in the pathogenesis of neuropathy, particularly in late onset cases.

Academic Significance and Societal Importance of the Research Achievements

遺伝子診断の進歩とともに家族性アミロイドポリニューロパチー(FAP)、特に高齢発症例は従来考えられていたよりも世界的に広範囲に存在すると考えられるようになっており、特に診断に難渋することの多い非集積地の高齢発症例に対する新規治療法の開発の重要性が高まっている。本研究の成果は、世界に先駆けてFAPの病態を従来型の集積地例における若年発症例と非集積地の高齢発症例を比較することによって明らかにするものであり、世界的にも注目されている。本研究によって明らかにされた病態、特に微小血管障害とアミロイド前駆体の毒性を抑制する治療戦略はFAP以外の疾患に対する新たな治療の確立にもつなげることが可能である。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (37 results)

All 2019 2018 2017

All Journal Article (18 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 18 results,  Open Access: 3 results) Presentation (19 results) (of which Int'l Joint Research: 17 results,  Invited: 6 results)

  • [Journal Article] Expanding the spectrum of transthyretin amyloidosis2019

    • Author(s)
      Koike Haruki、Katsuno Masahisa
    • Journal Title

      Muscle & Nerve

      Volume: 61 Issue: 1 Pages: 3-4

    • DOI

      10.1002/mus.26741

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease2019

    • Author(s)
      Adams David、Koike Haruki、Slama Michel、Coelho Teresa
    • Journal Title

      Nature Reviews Neurology

      Volume: 15 Issue: 7 Pages: 387-404

    • DOI

      10.1038/s41582-019-0210-4

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Ultrastructure in transthyretin amyloidosis: from pathophysiology to therapeutic insights2019

    • Author(s)
      Koike H, Katsuno M.
    • Journal Title

      Biomedicines

      Volume: 7 Issue: 1 Pages: 11-11

    • DOI

      10.3390/biomedicines7010011

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinicopathological spectrum and recent advances in the treatment of hereditary transthyretin amyloidosis2019

    • Author(s)
      Koike Haruki、Fukami Yuki、Nishi Ryoji、Kawagashira Yuichi、Iijima Masahiro、Sobue Gen、Katsuno Masahisa
    • Journal Title

      Neurology and Clinical Neuroscience

      Volume: 7 Pages: 166-173

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Common clinicopathological features in late-onset hereditary transthyretin amyloidosis (Ala97Gly, Val94Gly and Val30Met)2019

    • Author(s)
      Koike Haruki、Nakamura Tomohiko、Nishi Ryoji、Ikeda Shohei、Kawagashira Yuichi、Iijima Masahiro、Yasuda Takeshi、Mukai Eiichiro、Date Yukari、Shiomi Kazutaka、Nakazato Masamitsu、Katsuno Masahisa、Sobue Gen
    • Journal Title

      Amyloid

      Volume: 26 Issue: sup1 Pages: 24-25

    • DOI

      10.1080/13506129.2019.1582495

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evolution of amyloid fibrils in hereditary transthyretin amyloidosis: an ultrastructural study2019

    • Author(s)
      Koike Haruki、Nishi Ryoji、Ikeda Shohei、Kawagashira Yuichi、Iijima Masahiro、Katsuno Masahisa、Sobue Gen
    • Journal Title

      Amyloid

      Volume: 26 Issue: sup1 Pages: 26-26

    • DOI

      10.1080/13506129.2019.1582496

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cardiovascular autonomic functions in late-onset hereditary transthyretin amyloidosis with Val30Met mutation2019

    • Author(s)
      Nakamura Tomohiko、Koike Haruki、Nishi Ryoji、Ikeda Shohei、Kawagashira Yuichi、Iijima Masahiro、Katsuno Masahisa、Sobue Gen
    • Journal Title

      Amyloid

      Volume: 26 Issue: sup1 Pages: 6-6

    • DOI

      10.1080/13506129.2019.1582018

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cardiac and peripheral vasomotor autonomic functions in hereditary transthyretin amyloidosis with non-Val30Met mutation2019

    • Author(s)
      Koike Haruki、Nakamura Tomohiko、Nishi Ryoji、Ikeda Shohei、Kawagashira Yuichi、Iijima Masahiro、Katsuno Masahisa、Sobue Gen
    • Journal Title

      Amyloid

      Volume: 26 Issue: sup1 Pages: 13-14

    • DOI

      10.1080/13506129.2019.1582023

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Transthyretin amyloidosis: a model of medical progress for a fatal disease.2019

    • Author(s)
      Adams D, Koike H, Slama M, Coelho T.
    • Journal Title

      Nat Rev Neurol

      Volume: -

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Common clinicopathological features in late-onset hereditary transthyretin amyloidosis (Ala97Gly, Val94Gly, and Val30Met).2019

    • Author(s)
      Koike H, Nakamura T, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Yasuda T, Mukai E, Date Y, Shiomi K, Nakazato M, Katsuno M, Sobue G.
    • Journal Title

      Amyloid

      Volume: -

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Evolution of amyloid fibrils in hereditary transthyretin amyloidosis: an ultrastructural study.2019

    • Author(s)
      Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno M, Sobue G.
    • Journal Title

      Amyloid

      Volume: -

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cardiac and peripheral vasomotor autonomic functions in hereditary transthyretin amyloidosis with non-Val30Met mutation.2019

    • Author(s)
      Koike H, Nakamura T, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno M, Sobue G.
    • Journal Title

      Amyloid

      Volume: -

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cardiovascular autonomic functions in late-onset hereditary transthyretin amyloidosis with Val30Met mutation.2019

    • Author(s)
      Nakamura T, Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno M, Sobue G.
    • Journal Title

      Amyloid

      Volume: -

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Widespread Cardiac and Vasomotor Autonomic Dysfunction in Non-Val30Met Hereditary Transthyretin Amyloidosis2018

    • Author(s)
      Koike H, Nakamura T, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno M, Sobue G.
    • Journal Title

      Internal Medicine

      Volume: 57 Issue: 23 Pages: 3365-3370

    • DOI

      10.2169/internalmedicine.1113-18

    • NAID

      130007539665

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2018-12-01
    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The morphology of amyloid fibrils and their impact on tissue damage in hereditary transthyretin amyloidosis: An ultrastructural study.2018

    • Author(s)
      Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Sakurai T, Shimohata T, Katsuno M, Sobue G.
    • Journal Title

      J Neurol Sci

      Volume: 394 Pages: 99-106

    • DOI

      10.1016/j.jns.2018.09.011

    • NAID

      120006554498

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Systemic angiopathy and axonopathy in hereditary transthyretin amyloidosis with Ala97Gly (p. Ala117Gly) mutation: a post-mortem analysis.2018

    • Author(s)
      Koike H, Yasuda T, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Sobue G, Katsuno M.
    • Journal Title

      Amyloid

      Volume: 25 Issue: 2 Pages: 141-142

    • DOI

      10.1080/13506129.2018.1474734

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Disruption of blood-nerve barriers in hereditary transthyretin (ATTR) amyloidosis.2017

    • Author(s)
      Koike H, Ikeda S, Takahashi M, Kawagashira Y, Iijima M, Misumi Y, Ando Y, Ikeda SI, Katsuno M, Sobue G
    • Journal Title

      Amyloid

      Volume: 24(suppl) Issue: sup1 Pages: 89-90

    • DOI

      10.1080/13506129.2017.1278691

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cardiac and peripheral vasomotor autonomic functions in late-onset transthyretin Val30Met familial amyloid polyneuropathy.2017

    • Author(s)
      Koike H, Nakamura T, Hashizume A, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno M, Sobue G
    • Journal Title

      J Neurol

      Volume: 264 Issue: 11 Pages: 2293-2302

    • DOI

      10.1007/s00415-017-8629-2

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Familial amyloid polyneuropathy: from pathology and mechanisms of nerve degeneration to therapy.2019

    • Author(s)
      Koike H
    • Organizer
      The 3rd International Taiwanese Congress of Neurology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Pathology of familial amyloid polyneuropathy.2018

    • Author(s)
      Koike H
    • Organizer
      19th International congress of Neuropathology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Diagnosis and treatment of peripheral neuropathies.2018

    • Author(s)
      Koike H
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Vasculopathy in hereditary transthyretin amyloidosis: an electron microscopic study.2018

    • Author(s)
      Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Misumi Y, Ando Y, Ikeda SI, Katsu..no M, Sobue G
    • Organizer
      19th International congress of Neuropathology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Evolution of amyloid fibrils in transthyretin familial amyloid polyneuropathy: an ultrastructural study.2018

    • Author(s)
      Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno M, Sobue G
    • Organizer
      2018 Peripheral Nerve Society Annual Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Evolution of amyloid fibrils in hereditary ATTR amyloidosis:an ultrastructural study.2018

    • Author(s)
      Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno.M, Sobue G
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Common clinicopathological features in late-onset hereditary ATTR amyloidosis (Ala97Gly, Val94Gly, and Val30Met).2018

    • Author(s)
      Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Yasuda T, Mukai E, Date Y, Shiomi K, Nakazato M, Katsuno.M, Sobue G
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cardiac and peripheral vasomotor autonomic functions in hereditary ATTR amyloidosis with non-Val30Met mutation.2018

    • Author(s)
      Koike H, Nakamura T, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno.M, Sobue G
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cardiac and peripheral vasomotor autonomic functions in hereditary ATTR amyloidosis with Val30Met mutation.2018

    • Author(s)
      13.Nakamura T, Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno.M, Sobue G
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Patisiran, an investigational RNAi therapeutic for patients with hereditary transthyretin-mediated (hATTR) amyloidosis: Phase 3 APOLLO study subanalysis of Japanese patients.2018

    • Author(s)
      Yamashita Y, Sekijima Y, Koike H, Ueda M, Yoshinaga T, Kodaira M, Sobue G, Katsuno M, Singh T, Hashimoto Y, Kadam K, Hou A, Ando Y
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] First nationwide survey on systemic wild-type ATTR amyloidosis in Japan.2018

    • Author(s)
      Sekijima Y, Yazaki M, Ueda M, Koike H, Yamada M, Ando Y
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 末梢神経疾患をめぐる病態と治療法の新たな展開2018

    • Author(s)
      小池春樹
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 痛みの神経病理2018

    • Author(s)
      小池春樹
    • Organizer
      第29回日本末梢神経学会学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Diagnosis and treatment of peripheral neuropathies2018

    • Author(s)
      Koike H
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Evolution of amyloid fibrils in hereditary ATTR amyloidosis: an ultrastructural study2018

    • Author(s)
      Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno M, Sobue G
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Common clinicopathological features in late-onset hereditary ATTR amyloidosis (Ala97Gly, Val94Gly, and Val30Met)2018

    • Author(s)
      Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Yasuda T, Mukai E, Date Y, Shiomi K, Nakazato M, Katsuno M, Sobue G
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cardiac and peripheral vasomotor autonomic functions in hereditary ATTR amyloidosis with non-Val30Met mutation2018

    • Author(s)
      Koike H, Nakamura T, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno M, Sobue G
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cardiac and peripheral vasomotor autonomic functions in late-onset hereditary ATTR amyloidosis with Val30Met mutation2018

    • Author(s)
      Nakamura T, Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno M, Sobue G
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Schwann cell and endothelial cell damage in transthyretin familial amyloid polyneuropathy2017

    • Author(s)
      Koike H, Ikeda S, Takahashi M, Kawagashira Y, Iijima M, Misumi Y, Ando Y, Ikeda SI, Katsuno M, Sobue G
    • Organizer
      2017 PNS Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2021-02-19  

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