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Basic research on development of novel therapeutic products for hemophilia A and thrombotic disorders based on the regulation of factor VIII function in the blood coagulation

Research Project

Project/Area Number 21K07804
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionNara Medical University

Principal Investigator

Nogami Keiji  奈良県立医科大学, 医学部, 教授 (50326328)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords第VIII因子 / トロンビン / 第IX因子 / 凝固 / 遺伝子組み換え型 / インヒビター / ノックアウトマウス / 遺伝子組み換え蛋白 / 血友病 / 機能構造 / 遺伝子組換え蛋白 / 凝固機能 / FVIII / 遺伝子組み換え / 機能 / 結合 / 血友病マウス / 活性化 / 機能獲得型蛋白 / 包括的凝固機能
Outline of Research at the Start

血液凝固第Ⅷ因子は欠乏すると重篤な出血傾向(血友病A)、増加すると血栓傾向を示す血液凝固制御に重要な因子である。凝固を促進するにはトロンビンの第Ⅷ因子の活性化、凝固を抑制するには活性化された第Ⅷ因子の不安定性に加え、活性型プロテインCによる不活化が関与する。そのことから、本研究は第Ⅷ因子の各凝固蛋白の結合領域をターゲットにした改変した第Ⅷ因子蛋白を設計して作製し、本因子の作用が持続そして増強するタイプならびに第Ⅷ因子インヒビターへの反応が低下する、多くの機能を獲得した血友病Aに対する新規第Ⅷ因子製剤の開発、そして第Ⅷ因子関連機能制御からみた抗血栓薬の開発の基礎研究である。

Outline of Final Research Achievements

In coagulation factor Ⅷ (FⅧ), which is involved in both bleeding and hemostasis in blood coagulation, we identified a thrombin-binding region that regulates activation by FⅧ cleavage and successfully produced a highly active gain-of-function FⅧ protein focusing on this binding region. We identified a novel FⅨa-binding region on FⅧa in the intrinsic tenase complex, and also generated a high active-sustained FVIII protein focusing on the FVIIIa-FIXa interaction. In addition, an inhibitor-binding-avoiding FⅧ protein was also generated.

Academic Significance and Societal Importance of the Research Achievements

血液凝固第Ⅷ因子は出血と血栓の相反する病態に関わる重要な凝固因子であるため、今回の研究における第Ⅷ因子に関連した機能構造および他の凝固因子との相互反応の解明が、凝固や血栓形成機序の解明と血友病A患者への新規第Ⅷ因子治療製剤開発への応用、また第Ⅷ因子の生体内機能を制御する抗血栓および抗凝固薬の開発に将来的に繋がり、止血血栓学の発展並びに医療に貢献できるものと思われる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (18 results)

All 2024 2023 2022 2021

All Journal Article (10 results) (of which Peer Reviewed: 9 results,  Open Access: 1 results) Presentation (8 results) (of which Int'l Joint Research: 3 results,  Invited: 3 results)

  • [Journal Article] The emicizumab-bridged ternary complex with activated factor IX and factor X evaluated by fluorescence resonance energy transfer2024

    • Author(s)
      Oda A, Takeyama M, Kitazawa T, Nogami K.
    • Journal Title

      Thromb Res.

      Volume: 237 Pages: 108-111

    • DOI

      10.1016/j.thromres.2024.03.030

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The role of proteolytic cleavage at Arg336 and Arg372 of the A1 domain in factor VIIa/tissue factor-catalyzed reactions of B domain-deleted factor VIII2024

    • Author(s)
      Nakajima Y, Nogami K.
    • Journal Title

      Biochim Biophys Acta Gen Subj.

      Volume: 1868 Issue: 1 Pages: 130501-130501

    • DOI

      10.1016/j.bbagen.2023.130501

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hybrid human-porcine factor VIII proteins partially escape the inhibitory effects of anti-factor VIII inhibitor alloantibodies having A2 or C2 domain specificity2024

    • Author(s)
      Mizumachi K, Nakajima Y, Shimonishi N, Furukawa S, Ogiwara K, Takeyama M, Nogami K.
    • Journal Title

      Haemophilia

      Volume: 30 Issue: 1 Pages: 140-150

    • DOI

      10.1111/hae.14911

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Factor VIII A3 domain residues 1793-1795 represent a factor IXa-interactive site in the tenase complex2023

    • Author(s)
      Takeyama M, Furukawa S, Sasai K, Horiuchi K, Nogami K.
    • Journal Title

      Biochim Biophys Acta Gen Subj.

      Volume: 1867 Issue: 8 Pages: 130381-130381

    • DOI

      10.1016/j.bbagen.2023.130381

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Factor VIII mutated with Lys1813Ala within the factor IXa-binding region enhances intrinsic coagulation potential.2023

    • Author(s)
      Nakajima Y, Takeyama M, Oda A, Shimonishi N, Nogami K.
    • Journal Title

      Blood Advances

      Volume: 7 Issue: 8 Pages: 14361445-14361445

    • DOI

      10.1182/bloodadvances.2022008187

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Acidic Region Residues 1680-1684 in the A3 Domain of Factor VIII Contain a Thrombin-Interactive Site Responsible for Proteolytic Cleavage at Arg16892021

    • Author(s)
      Nakajima Y, Minami H, Nogami K.
    • Journal Title

      Thromb Haemost.

      Volume: - Issue: 10 Pages: 1274-1288

    • DOI

      10.1055/s-0041-1723996

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] The C-terminal acidic region in the A1 domain of factor VIII facilitates thrombin-catalyzed activation and cleavage at Arg 3722021

    • Author(s)
      Nakajima Y, Nogami K
    • Journal Title

      J Thromb Haemost.

      Volume: 19 Issue: 3 Pages: 677-688

    • DOI

      10.1111/jth.15201

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Inhibitor Index in the Clot Waveform Analysis-Based Mixing Test Differentiates among Hemophilia A without and with Inhibitors, and Lupus Anticoagulant.2021

    • Author(s)
      Shimonishi N, Ogiwara K, Oda Y, Kawabe T, Emmi M, Shima M, Nogami K.
    • Journal Title

      Thromb Haemost.

      Volume: 121 Issue: 06 Pages: 792-799

    • DOI

      10.1055/s-0040-1721776

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] A Novel Assessment of Factor VIII Activity by Template Matching Utilizing Weighted Average Parameters from Comprehensive Clot Waveform Analysis.2021

    • Author(s)
      Shimonishi N, Ogiwara K, Oda Y, Kawabe T, Okazaki S, Shima M, Nogami K.
    • Journal Title

      Thromb Haemost.

      Volume: 121 Issue: 02 Pages: 164-173

    • DOI

      10.1055/s-0040-1715838

    • Related Report
      2021 Research-status Report
  • [Journal Article] Ex Vivo Prediction of Comprehensive Coagulation Potential Using Simulated Blood Concentrations of Emicizumab in Patients with Acquired Hemophilia A.2021

    • Author(s)
      Takeyama M, Furukawa S, Yada K, Ogiwara K, Shimonishi N, Nakajima Y, Mizumachi K, Noguchi-Sasaki M, Shima M, Nogami K.
    • Journal Title

      Thromb Haemost.

      Volume: 121 Issue: 10 Pages: 1289-1298

    • DOI

      10.1055/s-0041-1725009

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] A2/C2 domain をブタ第VIII 因子相同配列に組み換えたhybrid ヒト第VIII 因子のインヒビター回避能2022

    • Author(s)
      水町 邦義,中島 由翔,下西 成人,古川 晶子,荻原 建一,武山 雅博,野上 恵嗣
    • Organizer
      第44回 日本血栓止血学会
    • Related Report
      2022 Research-status Report
  • [Presentation] Factor VIII K1813A has high affinity for activated factor IX and enhances global coagulation function2022

    • Author(s)
      Nakajima Y, Takeyama M, Oda A, Nogami K
    • Organizer
      International Society of Thrombosis and Hemostasis Congress 2022
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] A role of P'4 residue on cleavage at Arg372 and Arg1689 in thrombin-catalyzed factor VIII activation2022

    • Author(s)
      Furukawa S, Horiuchi K, Nogami K
    • Organizer
      第84回 日本血液学会
    • Related Report
      2022 Research-status Report
  • [Presentation] FVIII mutated with Lys1813Ala within the FIXa-binding region enhances coagulation potentials2022

    • Author(s)
      Nakajima Y, Takeyama M, Oda A, Nogami K
    • Organizer
      第84回 日本血液学会
    • Related Report
      2022 Research-status Report
  • [Presentation] Escaping ability of human-porcine hybrid factor VIII from anti-human factor VIII inhibitors with A2 or C2 epitope2022

    • Author(s)
      Mizumachi K, Nakajima Y, Shimonishi N Furukawa S, Ogiwara K, Takeyama M, Shima M, Nogami K
    • Organizer
      The 64th American Society of Hematology
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Latest Treatment for Hemophilia A and B in Japan2021

    • Author(s)
      Keiji Nogami
    • Organizer
      ICKSH
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Current topics on hemophilia and fibrinolysis system2021

    • Author(s)
      Keiji Nogami
    • Organizer
      日本血栓止血学会学術集会SPCシンポジウム
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 血友病治療の新展開2021

    • Author(s)
      野上恵嗣
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report
    • Invited

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Published: 2021-04-28   Modified: 2025-01-30  

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