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Development of therapeutic drugs fro achondroplasia-Examination of FGFR3 inhibitory effects of meclizine hydrochloride

Research Project

Project/Area Number 21H03063
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 56020:Orthopedics-related
Research InstitutionAichi Children’s Health and Medical Center

Principal Investigator

Kitoh Hiroshi  あいち小児保健医療総合センター(臨床研究室), 臨床研究室, 副センター長 (40291174)

Co-Investigator(Kenkyū-buntansha) 三島 健一  名古屋大学, 医学系研究科, 准教授 (40646519)
松下 雅樹  名古屋大学, 医学系研究科, 特任助教 (60721115)
細野 祥之  岡山大学, 医歯薬学域, 教授 (60820363)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2023: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2022: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2021: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
Keywords軟骨無形成症 / FGFR3 / 塩酸メクリジン / 骨伸長 / モデルマウス / ゼブラフィッシュモデル
Outline of Research at the Start

軟骨無形成症は四肢短縮型低身長を特徴とする骨系統疾患で、FGFR3の恒常的活性型変異により発症する。我々は既存薬の網羅的スクリーニングにより、塩酸メクリジンが軟骨系細胞においてFGFR3を抑制し、動物モデルにおいて骨伸長を促進することを示し、単回投与第1相治験を医師主導で実施した。本研究では、①FGFR3下流のシグナル経路における作用機序の解明 ②ACHモデルマウスにおいて骨伸長促進作用を示す至適投与量の決定 ③ゼブラフィッシュACHモデルの確立と、発生・分化・成長の各段階におけるメクリジンの作用の検討、の3つの基礎研究を実施し、医師主導第2相治験に資する本剤の薬理作用データを蓄積する。

Outline of Final Research Achievements

From mechanism of action studies, meclizine suppressed FGFR3 signaling through inhibition of intracellular MAP3K3 pathway in chondrocytes. We next performed docking simulations of MAP3K3 and meclizine and identified the two co-binding structures. From in vivo studies, we identified that 2mg/kg/day of meclizine provided the greatest effect on longitudinal bone growth in ACH mice. In addition, we performed long-term administration of meclizine and demonstrated that the survival rate of model mice was improved by spinal canal stenosis being rescued. Meclizine also enhanced mineralization and improved histological structure in growth plates of Hyp mice. From zebrafish experiments, meclizine inhibited bone calcification in the spine and skull that was activated by the FGF signaling.

Academic Significance and Societal Importance of the Research Achievements

軟骨無形成症(ACH)に対する病態に即した治療薬であるボソリチドが2022年に本邦でも承認され、多くのACH患者に投与されている。しかし連日の皮下注射による長期にわたる投与は小児にとっては負担が大きい。塩酸メクリジンは経口内服剤であり、小児患者における長期投与のコンプライアンスが期待できる。我々は実用化に向け、メクリジンをACH小児に投与する第2相医師主導治験をすでに実施したが、本研究ではメクリジンの分子レベルでのFGFR3に対する抑制作用を明らかにする基礎研究と、モデルマウスを用いた動物実験を組み合わせ、メクリジンによるFGFR3抑制作用に関する基礎的エビデンスを蓄積した。

Report

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

    (51 results)

All 2024 2023 2022 2021

All Journal Article (18 results) (of which Peer Reviewed: 18 results,  Open Access: 9 results) Presentation (31 results) (of which Int'l Joint Research: 9 results,  Invited: 17 results) Book (2 results)

  • [Journal Article] Long-term oral meclozine administration improves survival rate and spinal canal stenosis during postnatal growth in a mouse model of achondroplasia in both sexes2024

    • Author(s)
      Funahashi Hiroto、Matsushita Masaki、Esaki Ryusaku、Mishima Kenichi、Ohkawara Bisei、Kamiya Yasunari、Takegami Yasuhiko、Ohno Kinji、Kitoh Hiroshi、Imagama Shiro
    • Journal Title

      JBMR Plus

      Volume: 8 Issue: 4

    • DOI

      10.1093/jbmrpl/ziae018

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phase 1b study on the repurposing of meclizine hydrochloride for children with achondroplasia2023

    • Author(s)
      Matsushita Masaki、Kitoh Hiroshi、Mishima Kenichi、Kamiya Yasunari、Kato Daisaku、Takemoto Genta、Sawamura Kenta、Ueno Shinji、Yasuhiro Nakai、Nishida Kazuki、Imagama Shiro
    • Journal Title

      PLOS ONE

      Volume: 18 Issue: 7 Pages: e0283425-e0283425

    • DOI

      10.1371/journal.pone.0283425

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Orthopaedic manifestations in childhood-onset Satoyoshi syndrome: A case report.2023

    • Author(s)
      Sawamura K, Kitoh H, Abe N, Atobe M, Kaneko H, Kitamura A
    • Journal Title

      JOS Case Rep

      Volume: 2 Pages: 135-139

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Changes of the lower limb deformity in children with FGF23-related hypophosphatemic rickets treated with Burosumab: a single-center prospective study2023

    • Author(s)
      Sawamura Kenta、Hamajima Takashi、Izawa Masako、Kaneko Hiroshi、Kitamura Akiko、Kitoh Hiroshi
    • Journal Title

      Journal of Pediatric Orthopaedics B

      Volume: 33 Issue: 1 Pages: 90-96

    • DOI

      10.1097/bpb.0000000000001054

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activated FGFR3 suppresses bone regeneration and bone mineralization in an ovariectomized mouse model2023

    • Author(s)
      Kawashima Itaru、Matsushita Masaki、Mishima Kenichi、Kamiya Yasunari、Osawa Yusuke、Ohkawara Bisei、Ohno Kinji、Kitoh Hiroshi、Imagama Shiro
    • Journal Title

      BMC Musculoskeletal Disorders

      Volume: 24 Issue: 1 Pages: 200-200

    • DOI

      10.1186/s12891-023-06318-9

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Guided growth for coronal lower limb deformities in skeletal dysplasia.2022

    • Author(s)
      Kitoh H, Kamiya Y, Mishima K, Matsushita M, Kaneko H, Kitamura A, Sawamura K, Matsuyama S
    • Journal Title

      J Pediatr Orthop B

      Volume: - Issue: 2 Pages: 157-164

    • DOI

      10.1097/bpb.0000000000000965

    • Related Report
      2023 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Femoral lengthening with enzyme replacement therapy in an adolescent patient with prenatal benign hypophosphatasia: A case report.2022

    • Author(s)
      Kitoh H, Kaneko H, Kitamura A, Sawamura K
    • Journal Title

      J Orthop Sci

      Volume: - Issue: 6 Pages: 1487-1491

    • DOI

      10.1016/j.jos.2021.07.010

    • Related Report
      2023 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Meclozine ameliorates bone mineralization and growth plate structure in a mouse model of X-linked hypophosphatemia2022

    • Author(s)
      Kamiya Yasunari、Matsushita Masaki、Mishima Kenichi、Ohkawara Bisei、Michigami Toshimi、Imagama Shiro、Ohno Kinji、Kitoh Hiroshi
    • Journal Title

      Experimental and Therapeutic Medicine

      Volume: 25 Issue: 1 Pages: 39-39

    • DOI

      10.3892/etm.2022.11738

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gain-of-Function of FGFR3 Accelerates Bone Repair Following Ischemic Osteonecrosis in Juvenile Mice2022

    • Author(s)
      Kato Daisaku、Matsushita Masaki、Takegami Yasuhiko、Mishima Kenichi、Kamiya Nobuhiro、Osawa Yusuke、Imagama Shiro、Kitoh Hiroshi
    • Journal Title

      Calcified Tissue International

      Volume: 111 Issue: 6 Pages: 622-633

    • DOI

      10.1007/s00223-022-01019-2

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Disease-specific complications and multidisciplinary interventions in achondroplasia.2022

    • Author(s)
      Kitoh H, Matsushita M, Mishima K, Kamiya Y, Sawamura K
    • Journal Title

      J Bone Miner Metab

      Volume: 40 Issue: 2 Pages: 189-195

    • DOI

      10.1007/s00774-021-01298-z

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inconvenience and adaptation in Japanese adult achondroplasia and hypochondroplasia: A cross-sectional study2022

    • Author(s)
      Ajimi A, Matsushita M, Mishima K, Haga N, Fujiwara S, Ozono K, Kubota T, Kitaoka T, Imagama S, Kitoh H
    • Journal Title

      Clinical Pediatric Endocrinology

      Volume: 31 Issue: 1 Pages: 18-24

    • DOI

      10.1297/cpe.2021-0043

    • NAID

      130008138931

    • ISSN
      0918-5739, 1347-7358
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish2022

    • Author(s)
      Takemoto Genta、Matsushita Masaki、Okamoto Takaaki、Ito Toshinari、Matsuura Yuki、Takashima Chieko、Chen-Yoshikawa Toyofumi Fengshi、Ebi Hiromichi、Imagama Shiro、Kitoh Hiroshi、Ohno Kinji、Hosono Yasuyuki
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 9 Pages: 694018-694018

    • DOI

      10.3389/fcell.2021.694018

    • NAID

      120007190703

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A cross-sectional nationwide survey of osteosclerotic skeletal dysplasia in Japan.2022

    • Author(s)
      Sawamura K, Mishima K, Matsushita M, Kamiya Y, Kitoh H
    • Journal Title

      J Orthop Sci

      Volume: - Issue: 5 Pages: 1139-1142

    • DOI

      10.1016/j.jos.2021.05.012

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bypass of epiphyseal fragmentation following early Salter innominate osteotomy and its clinical relevance in Legg-Calve-Perthes disease.2022

    • Author(s)
      Mishima K, Kamiya Y, Matsushita M, Imagama S, Kitoh H
    • Journal Title

      J Pediatr Orthop

      Volume: 42 Issue: 5 Pages: 239-245

    • DOI

      10.1097/bpo.0000000000002089

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Predictive ability of inflammatory markers and laboratory parameters in Legg-Calve-Perthes disease: A single-center retrospective comparative study.2022

    • Author(s)
      Mishima K, Kamiya Y, Matsushita M, Imagama S, Kitoh H
    • Journal Title

      Medicine

      Volume: 101 Issue: 11

    • DOI

      10.1097/md.0000000000029061

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Asfotase alfa has a limited effect in improving the bowed limbs in perinatal benign hypophosphatasia: A case report2021

    • Author(s)
      Matsushita M, Mishima K, Nagata T, Kamiya Y, Imagama S, Kitoh H
    • Journal Title

      Clin Pediatr Endocrinol

      Volume: 30 Issue: 1 Pages: 53-56

    • DOI

      10.1297/cpe.30.53

    • NAID

      130007966048

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Docking phenomenon and subsequent acetabular development after gradual reduction using overhead traction for developmental dysplasia of the hip over six months of age.2021

    • Author(s)
      Kaneko H, Kitoh H, Kitamura A, Sawamura K, Hattori T
    • Journal Title

      J Child Orthop

      Volume: 15 Issue: 6 Pages: 554-563

    • DOI

      10.1302/1863-2548.15.210143

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Health-related Quality of Life in Adult Patients with Multiple Epiphyseal Dysplasia and Spondyloepiphyseal Dysplasia2021

    • Author(s)
      Matsushita M, Mishima K, Kamiya Y, Haga N, Fujiwara S, Ozono K, Kubota T, Kitaoka T, Imagama S, Kitoh H
    • Journal Title

      Progress in Rehabilitation Medicine

      Volume: 6 Issue: 0 Pages: n/a

    • DOI

      10.2490/prm.20210048

    • NAID

      130008125972

    • ISSN
      2432-1354
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 治療可能な骨系統疾患2024

    • Author(s)
      鬼頭浩史
    • Organizer
      第39回九州小児整形外科集談会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 軟骨無形成症と誤診した軟骨低形成症の2例2024

    • Author(s)
      鬼頭浩史
    • Organizer
      第5回東海地区骨系統疾患研究会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Bone dysplasias -An overview-2024

    • Author(s)
      Hiroshi Kitoh
    • Organizer
      23rd Asia Pacific Orthopaedic Association Congress
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Bone dysplasia -Radiographic findings for diagnosis-2024

    • Author(s)
      Hiroshi Kitoh
    • Organizer
      23rd Asia Pacific Orthopaedic Association Congress
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 低ホスファターゼ症―治療可能な難治性骨疾患―2023

    • Author(s)
      鬼頭浩史
    • Organizer
      第96回日本整形外科学会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 小児下肢変形の鑑別診断2023

    • Author(s)
      鬼頭浩史
    • Organizer
      小児科・整形外科に潜むFGF23関連疾患を考える会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 名古屋大学系列におけるDDH治療―装具治療のこれまでと今後―2023

    • Author(s)
      鬼頭浩史
    • Organizer
      第62回小児股関節研究会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 小児の下肢変形をきたす疾患2023

    • Author(s)
      鬼頭浩史
    • Organizer
      日常診療に潜む疾患-代謝性骨疾患UP TO DATE in 青森
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 骨系統疾患、麻痺性疾患の股関節障害2023

    • Author(s)
      鬼頭浩史
    • Organizer
      第9回日本股関節学会教育研修セミナー
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 骨系統疾患マニュアルアップデートと治療可能な稀少疾患-低ホスファターゼ症-2023

    • Author(s)
      鬼頭浩史
    • Organizer
      第34回日本小児整形外科学会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Pediatric orthopaedist perspective: Steps to diagnose and surgical management of skeletal dysplasia in Japan2023

    • Author(s)
      Hiroshi Kitoh
    • Organizer
      The 2nd Korea Skeletal Dysplasia Symposium
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Case studies on diagnosing patients with skeletal dysplasia2023

    • Author(s)
      Hiroshi Kitoh
    • Organizer
      The 2nd Korea Skeletal Dysplasia Symposium
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 診断に難渋した小児運動器疾患2023

    • Author(s)
      鬼頭浩史
    • Organizer
      第4回沖縄小児整形外科講習会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Long-term administration of meclozine for the treatment of achondroplasia using a mouse model2023

    • Author(s)
      Funahashi H, Matsushita M, Mishima K, Okawara B, Kamiya Y, Ohno K, Kitoh H, Imagama S
    • Organizer
      Orthopaedic Research Society 2023 Annual Meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] FGFR3シグナルは若年マウスの阻血性骨壊死の骨修復を加速する2023

    • Author(s)
      加藤大策、松下雅樹、竹上靖彦、三島健一、神谷宣広、大澤郁介、今釜史郎、鬼頭浩史
    • Organizer
      第35回日本軟骨代謝学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 軟骨無形成症における整形外科的な問題2022

    • Author(s)
      鬼頭浩史
    • Organizer
      第95回日本整形外科学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 軟骨無形成症患児を対象としたFGFR3シグナル抑制薬投与第1相治験2022

    • Author(s)
      松下雅樹、三島健一、神谷庸成、加藤大策、竹本元大、今釜史郎、鬼頭浩史
    • Organizer
      第95回日本整形外科学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 骨系統疾患―最新の話題―2022

    • Author(s)
      鬼頭浩史
    • Organizer
      第10回中国四国小児整形外科研究会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 軟骨無形成症患児を対象としたFGFR3シグナルを抑制する内服薬の14日間投与治験2022

    • Author(s)
      松下雅樹、鬼頭浩史、三島健一、神谷庸成、澤村健太、今釜史郎
    • Organizer
      第33回日本小児整形外科学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 小児運動器疾患における診断遅延例2022

    • Author(s)
      鬼頭浩史、金子浩史、北村暁子、澤村健太、松山沙織
    • Organizer
      第78回あいち小児医療懇話会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 日常診療で注意すべき骨系統疾患2022

    • Author(s)
      鬼頭浩史
    • Organizer
      第3回東海地区骨系統疾患研究会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 胎児CTによる骨系統疾患の出生前診断.2022

    • Author(s)
      鬼頭浩史
    • Organizer
      第3回東海地区骨系統疾患研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 診断に難渋した小児運動器疾患.2022

    • Author(s)
      鬼頭浩史
    • Organizer
      第20回知多半島整形外科連携セミナー
    • Related Report
      2021 Annual Research Report
  • [Presentation] Raising clinical suspicion of skeletal dysplasia: The application of gene panel testing to facilitate early diagnosis, Case study sharing from Japan.2021

    • Author(s)
      Kitoh H
    • Organizer
      BioMarin Expert Meeting
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Guided growth: Approach for skeletal dysplasia.2021

    • Author(s)
      Kitoh H, Kaneko H, Mishima K, Matsushita M, Kitamura A, Kamiya Y, Sawamura S
    • Organizer
      13th Combined Meeting of Asia Pacific Spine Society & Asia Pacific Paediatric Orthopaedic Society.
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Clinical and radiographic pitcome of Salter innominate osteotomy for incidentally discovered acetabular dysplasia.2021

    • Author(s)
      Sawamura K, Kitoh H, Kaneko H, Kitamura A
    • Organizer
      13th Combined Meeting of Asia Pacific Spine Society & Asia Pacific Paediatric Orthopaedic Society.
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The role of the Salter innominate osteotomy in Legg-Calve-Perthes disease.2021

    • Author(s)
      Mishima K, Kaneko H, Matsushita M, Kamiya Y, Imagama S, Kitoh H
    • Organizer
      13th Combined Meeting of Asia Pacific Spine Society & Asia Pacific Paediatric Orthopaedic Society.
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Health-related quality of life in patients with multiple epiphyseal dysplasia and spondyloepiphyseal dysplasia.2021

    • Author(s)
      Matsushita M, Mishima K, Kamiya Y, Haga N, Fujiwara S, Ozono K, Kubota T, KItaoka T, Imagama S, Kitoh H
    • Organizer
      13th Combined Meeting of Asia Pacific Spine Society & Asia Pacific Paediatric Orthopaedic Society
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 酵素補充療法を併用して大腿骨延長を行った周産期良性型低ホスファターゼ症の1例.2021

    • Author(s)
      鬼頭浩史、金子浩史、北村暁子、澤村健太
    • Organizer
      第14回ALPS研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ドラッグリポジショニングによる軟骨無形成症に対する治療薬開発.2021

    • Author(s)
      鬼頭浩史、松下雅樹、三島健一、神谷庸成、金子浩史、北村暁子、澤村健太
    • Organizer
      第39回日本骨代謝学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 小児難治性運動器疾患に対する薬物アプローチ.2021

    • Author(s)
      鬼頭浩史、三島健一、松下雅樹、神谷庸成、金子浩史、北村暁子、澤村健太
    • Organizer
      第36回日本整形外科学会基礎学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Book] Clinical aspects and current therapeutic approaches for fibrodysplasia ossificans progressive. Advanced in surgical and medical specialties.2023

    • Author(s)
      Hiroshi Kitoh
    • Total Pages
      1371
    • Publisher
      Jenny Stanford Publishing
    • Related Report
      2023 Annual Research Report
  • [Book] 骨系統疾患マニュアル2022

    • Author(s)
      鬼頭浩史
    • Total Pages
      219
    • Publisher
      南江堂
    • Related Report
      2022 Annual Research Report

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

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