JPWO2014141847A1 - 骨系統疾患治療薬及びその用途 - Google Patents
骨系統疾患治療薬及びその用途 Download PDFInfo
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Abstract
Description
以下に示す本願発明は、主として上記知見及び考察に基づく。
[1]メクリジン又はその薬学的に許容される塩を有効成分として含有する、線維芽細胞成長因子受容体3(FGFR3)の過剰な活性化に起因する骨系統疾患の治療薬。
[2]骨系統疾患が、軟骨無形成症、軟骨低形成症、タナトフォリック骨異形成症、クルーゾン病、遠位中間肢異形成症及び発達遅延と黒色表皮腫を伴う重度の軟骨無形成症(SADDAN)からなる群より選択される疾患である、[1]に記載の治療薬。
[3]有効成分が塩酸メクリジンである、[1]又は[2]に記載の治療薬。
[4]メクリジン又はその薬学的に許容される塩を治療上有効量、線維芽細胞成長因子受容体3(FGFR3)の過剰な活性化に起因する骨系統疾患の患者に投与するステップを含む、骨系統疾患の治療法。
[5]メクリジン又はその薬学的に許容される塩を有効成分として含有する、身長促進剤。
[6][5]に記載の身長促進剤を含有する身長促進用組成物。
[7]医薬、医薬部外品又は食品である、[6]に記載の身長促進用組成物。
(1)ラット軟骨肉腫(rat chondrosarcoma(RCS))細胞を用いた、1,186種類のFDA認可薬からのスクリーニング
Pavel Krejci博士(Medical Genetics Institute, Cedars-Sinai Medical Center, LA)より供与されたRCS細胞を、10%ウシ胎仔血清(FBS, Thermo Scientific)を添加したダルベッコ変法イーグル培地(DMEM, Invitrogen)で培養した(参考文献14)。RSC増殖アッセイ(growth arrest assay)のために、約5×103個の細胞を96ウェル培養プレート(Falcon)に播種し、10μMのFDA認可薬(1,186種類。Prestwick Chemical)と5 ng/mlのFGF2(R&D Systems)の存在下、48時間、培養した。MTSアッセイ(Cell 96 AQueus One Solution Cell Proliferation Assay, Promega)により細胞の増殖を定量した。操作は添付のマニュアルに従った。
アルシアンブルー染色のために、12ウェルプレートでRCS細胞を培養し、各ウェルに5 ng/mlのFGF2と10μMのメクリジン又は0.2μMのCNP(Calbiochem)を添加した。72時間後、細胞をメタノールで固定化し(-20℃、30分間)、1 N HClで溶解した0.5% Alcian Blue 8 GX (Sigma)で染色した(overnight)。定量分析のために、アルシアンブルーで染色した細胞を室温にて6時間、200μlの6 Mグアニジン塩酸で抽出した(参考文献28)。PowerScan 4(DS Pharma Biomedical)を使用し、抽出されたアルシアンブルーの光学的濃度(610nmでの吸光度)を測定した。
20μMのメクリジン又は0.2μMのCNPの存在下、FGF2で処理したRSC細胞からTrizolを用いて全RNAを単離した。ReverTra Ace(Toyobo)を使用して第一鎖cDNAを合成した。LightCycler 480 Real-Time PCR (Roche)とSYBR Green(Takara)を利用してマトリックスプロテアーゼ(Mmp10、Mmp13、Adamts1)のmRNAレベルを定量した。尚、測定値はGapdhのmRNA発現レベルで補正した。
野生型FGFR3を発現するベクターpRK7-FGFR3-WTと変異型FGFR3(参考文献29)を発現するベクターpRK7-FGFR3-K650E及びpRK7-FGFR3-K650MはPavel Krejci博士(Medical Genetics Institute, Cedars-Sinai Medical Center, LA)より供与された。QuikChange site-directed mutagenesis kit(Stratagene)を用いてpRK7-FGFR3-G380Rを調製した。制限酵素HindIII及びBamHIによる処理により、野生型FGFR3 cDNAと変異型FGFR3 cDNAをベクターから切り出した。NheIサイト及びBamHIサイトを利用して各断片をレンチウイルスベクターCSII-CMV-MCS-IRES2-Venusにクローニングした。CSII-CMV-MCS-IRES2-Venusは三好浩之博士(Riken BioResource Center, Tsukuba, Japan.)より供与された。ライゲーションに先立ち、Quick Blunting Kit(New England Biolabs)を用いてインサートのHindIIIサイトとベクターのNheIサイトを平滑化した。トランスフェクションの前日にHEK293細胞を150mmディッシュに播種した。Lipofectamine 2000(Invitrogen)を用い、pLP1プラスミド、pLP2プラスミド、pLP/VSVGプラスミド(ViraPower Packaging Mix, Invitrogen)とCSII-CMV-MCS-IRES2-VenusベクターをHEK293に導入した。操作は添付のマニュアルに従った。トランスフェクション48時間後に、ウイルス粒子を含む培養液をMillex-HV 0.45 μm PVDFフィルター(Millex)を用いてフィルター処理し、2段階の超遠心処理(Beckman Coulter)によってレンチウイルスを精製した。精製したレンチウイルスをHCS-2/8細胞又はATDC5細胞の培養液に添加した。48時間後、90%以上の細胞がウイルスシグナル陽性であることを確認した。
レンチウイルス(FGFR3-WT、FGFR3-K650E又はFGFR3-K650Mを発現する)をHCS-2/8(参考文献31)細胞に感染させ、96ウェル培養プレートに約5×103個播種した。48時間後、MTSアッセイによって細胞数を測定した。また、HCS-2/8細胞にFGFR3-K650Eを発現するレンチウイルスを導入し、12ウェルプレートに約1×105個播種した。72時間後、Venusタンパク質の蛍光強度をArrayScan VTI HCS Reader(Thermo Scientific)で定量した。
レンチウイルス(FGFR3-WT又はFGFR3-G380Rを発現する)をマウス胚性癌腫由来ATDC5細胞(参考文献32)に感染させた。感染後の細胞を微小塊培養(参考文献33)に供した。概要を述べれば、5% FBSを含有するDMEM/F-12(1:1)培地(Sigma)に1×107 cells/mlの濃度でATDC5細胞を懸濁し、高濃度軟骨凝縮を模倣すべく10μlの液滴で播種した。1時間のインキュベーションの後、1% インスリン−トランスフェリン−亜セレン酸ナトリウム(ITS, Sigma)を添加した培地を添加した。6日目に細胞を回収するまで、1日おきに培地を交換した。
器官培養のために、顕微鏡下、野生型マウス胎仔(E16.5)の脛骨を採取し、96ウェル培養プレートに移した後、0.2%ウシ血清アルブミン、1 mM β-glycerophosphate及び50μg/mlアスコルビン酸を添加したα-minimal essential medium(Invitrogen)で培養した。続いて、20μMメクリジン又は0.2μM CNPの存在下及び非存在下において、100 ng/ml FGF2で6日間処理し、10% ホルムアルデヒド(リン酸緩衝液内)で固定した。0.5 M EDTAで脱ミネラル化し、パラフィン包埋した。切片をヘマトキシリンエオジン及びアルシアンブルーで染色した後、XZ-1デジタルカメラ(Olympus)を装着したSZ61顕微鏡(Olympus)で撮影した。骨の長径の長さ(関節軟骨の基部−先端部間の長さとして定義される)をImageJ (NIH)を用いて測定した。
RCS細胞を20μMメクリジンで30分間処理した(メクリジン非処理細胞をVehicleとした)。5 ng/ml FGF2を添加し、5分後、プロテアーゼインヒビターを添加した氷冷RIPA Lysis Buffer (Santa Cruz)で細胞を融解した。全細胞ライセートをSDS-PAGEで分離し、ニトロセルロース膜に転写した。以下の抗体、即ちERK1/2、リン酸化-ERK1/2(Thr202/ Tyr204)、MEK1/2、及びリン酸化-MEK1/2(Ser217/221) (Cell Signaling)を使用して、MAPK経路における各分子のリン酸化レベルをウエスタンブロットで決定した。
正常の妊娠マウスに妊娠14日目からメクリジンを内服投与し(5gの餌にメクリジン2mgを含有)、生後5日目の仔マウスの体長、肢長を評価した。一方、正常マウスに生後2週からメクリジンを内服投与し、5週目で同様に評価した。
(1)メクリジンはRCS細胞においてFGF2による増殖抑制と細胞外マトリクス喪失をレスキューする
ラット軟骨肉腫(RCS)細胞はFGFR3を高発現しているため、FGF2を添加すると軟骨無(低)形成症の成長軟骨でみられる特徴をin vitroで再現できる(参考文献22)。FGF2 (5 ng/ml)を加えたRCS細胞に1,186種類のFDA認可薬(Prestwick Chemical)をそれぞれ10μM添加した。RCS細胞の増殖能をMTSアッセイで定量した結果、メクリジンを添加するとvehicleと比較して1.4倍以上の細胞増殖能が再現性をもって示された。さらに、0、1、2、5、10、20、50μMのメクリジンを添加するとRCSの細胞増殖能は濃度依存性に増加したが、50μMで毒性が認められた(図1A)。
次に、レンチウイルスを用いてFGFR3の変異型(K650E:致死性異形成症、K650M:SADDAN)を導入したヒト軟骨肉腫(human chondrosarcoma)細胞(HCS-2/8)において、メクリジンによるFGFR3シグナル抑制効果を検証した。K650Eを導入したHCS-2/8は有意に細胞増殖能が低下したことをMTSアッセイで確認した(図2A)。K650EまたはK650Mが発現したいずれのHCS-2/8においてもメクリジン(20μM)は増殖抑制を一部阻害した(図2B)。さらに、細胞内に発現しているVenusの蛍光強度比較することでも、K650Eが導入されたHCS-2/8はメクリジンにより細胞増殖が促進されることが分かった(図2C)。
ATDC5細胞は軟骨分化能を有するため軟骨分化過程をin vitroで解析するのによく用いられている(参考文献15)。軟骨無形成症の成長軟骨では分化抑制が起きることが知られており、FGFR3の変異型(G380R:軟骨無形成症)をレンチウイルスにて導入したATDC5細胞の微小塊培養(micromass culture)にメクリジン(20μM)を加えて分化誘導を行うことにより、メクリジンが軟骨の分化抑制をレスキューできるか否か検証した。FGFR3の野生型を導入したATDC5細胞ではアルシアンブルーの染色性が良好であるのに対し、変異型を導入したATDC5細胞では染色性が低下する。この変異型を導入したATCD5細胞にメクリジンを添加するとアルシアンブルーの染色性がレスキューされた。次に、アルシアンブルー染色後にグアニジン塩酸を加え610 nmの吸光度測定し染色性の定量を行った。変異型を導入したATDC5では吸光度の低下が認められたが、これをメクリジンがレスキューした(図3)。以上より、メクリジンはFGFR3変異型の導入による軟骨分化抑制効果をレスキューする。
胎仔脛骨にFGF2を添加し器官培養を行うと骨の長径成長が抑制されることが知られているが(参考文献14)、FGF2と同時にメクリジンを投与すると成長抑制がレスキューされるかどうか検証した。FGF2(100 ng/ml)と同時にCNP(0.2μM)またはメクリジン(20μM)を器官培養液に加え、骨の長さを同一個体の反対側と比較した。FGF2を添加し6日間器官培養を行うと胎仔脛骨の長径成長は抑制され、CNPとメクリジンはFGF2による骨の成長抑制を有意にレスキューした(図4)。さらに、メクリジンはFGF2を添加しない脛骨の長径成長も促進した。
RCS細胞を用いてFGFR3シグナルにおけるメクリジンの効果を検証した。RCS細胞に対してFGF2添加30分前にメクリジンを投与し、ウエスタンブロッティング法にてERKとMEKのリン酸化レベルを評価した。メクリジンはFGF2添加によるERK1/2のリン酸化を抑制したが、MEK1/2のリン酸化を抑制しなかった(図5A)。さらに、恒常的にシグナルが活性化したERK、MEK、RAFのそれぞれの変異型をレンチウイルスによりRCSに導入し、細胞増殖能をMTSアッセイにより評価した。メクリジンは活性化したMEKとRAFによる増殖抑制をレスキューした一方、ERKによる増殖抑制を阻害する効果は認められなかった(図5B)。以上より、メクリジンはリン酸化MEKによるERKのリン酸化の抑制、またはERKのリン酸化酵素の活性を抑制することが示唆された(図6)。
正常の妊娠マウスに妊娠14日目からメクリジンを内服投与し、生後5日目の仔マウスを評価したところ、メクリジン投与群において体長、上肢長及び下肢長の増大を認めた(図7)。また、正常マウスに生後2週からメクリジンを投与し、5週目で評価したところ、メクリジン投与群において体長及び尾長の増大を認めた(図8)。
Drug Repositioningは既存薬の新たな効能を発見する手法であり、候補薬を段階的に絞り込んでいく手順により研究の経費と時間を削減できることがメリットである(参考文献20、23)。有用性と毒性がすでに担保されている1,186種類のFDA認可薬のなかで、メクリジンは新規のFGFR3シグナル阻害薬であり、軟骨無(低)形成症における低身長の治療薬として臨床応用される可能性を秘めている。メクリジンは抗ヒスタミン作用を有し、乗り物酔い止め薬としてOTC(over the counter)販売されており、50年以上安全に使用されてきた実績がある。したがって至適服用量・副作用・禁忌など安全性が確立されており、この薬剤が臨床応用可能な濃度においてFGFR3の抑制効果を示せば、そのまま臨床応用ができる可能性が高い。
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Claims (7)
- メクリジン又はその薬学的に許容される塩を有効成分として含有する、線維芽細胞成長因子受容体3(FGFR3)の過剰な活性化に起因する骨系統疾患の治療薬。
- 骨系統疾患が、軟骨無形成症、軟骨低形成症、タナトフォリック骨異形成症、クルーゾン病、遠位中間肢異形成症及び発達遅延と黒色表皮腫を伴う重度の軟骨無形成症(SADDAN)からなる群より選択される疾患である、請求項1に記載の治療薬。
- 有効成分が塩酸メクリジンである、請求項1又は2に記載の治療薬。
- メクリジン又はその薬学的に許容される塩を治療上有効量、線維芽細胞成長因子受容体3(FGFR3)の過剰な活性化に起因する骨系統疾患の患者に投与するステップを含む、骨系統疾患の治療法。
- メクリジン又はその薬学的に許容される塩を有効成分として含有する、身長促進剤。
- 請求項5に記載の身長促進剤を含有する身長促進用組成物。
- 医薬、医薬部外品又は食品である、請求項6に記載の身長促進用組成物。
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WO2023117855A1 (en) * | 2021-12-20 | 2023-06-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of analog of c-type natriuretic peptide for the treatment of fgfr-related bone repair and bone formation impairment |
WO2024029173A1 (ja) * | 2022-08-03 | 2024-02-08 | 国立大学法人東海国立大学機構 | 骨粗鬆症の予防又は改善剤 |
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JPH08239327A (ja) * | 1995-03-03 | 1996-09-17 | Taisho Pharmaceut Co Ltd | 慢性骨格筋疼痛の予防又は治療剤 |
WO2007061130A1 (ja) * | 2005-11-22 | 2007-05-31 | Eisai R & D Management Co., Ltd. | 多発性骨髄腫に対する抗腫瘍剤 |
US7291461B2 (en) * | 2002-06-21 | 2007-11-06 | Ptc Therapeutics, Inc. | Methods for identifying small molecules that modulate premature translation termination and nonsense mRNA decay |
JP2008533111A (ja) * | 2005-03-16 | 2008-08-21 | サノフイ−アベンテイス | 新規イミダゾ[1,5−a]ピリジン誘導体、該誘導体を調製する方法及び該誘導体を含有する医薬組成物 |
JP2009520768A (ja) * | 2005-12-21 | 2009-05-28 | ノバルティス アクチエンゲゼルシャフト | Fgf阻害剤であるピリミジニルアリールウレア誘導体 |
WO2011150859A1 (en) * | 2010-06-04 | 2011-12-08 | Comprehensive Drug Enterprises Ltd | Oral meclizine aqueous formulations with taste flavoring agent |
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IL122472A (en) | 1995-06-12 | 2003-11-23 | Yeda Res & Dev | Compositions of fgf9 as a specific ligand for fgfr3 and uses thereof |
JP2003104908A (ja) | 2001-09-28 | 2003-04-09 | Ichikazu Nakao | 軟骨無形成症治療剤 |
WO2009067639A2 (en) | 2007-11-21 | 2009-05-28 | Biomarin Pharmaceutical Inc. | Variants of c-type natriuretic peptide |
DK3175863T3 (da) * | 2009-05-20 | 2022-02-07 | Biomarin Pharm Inc | Varianter af c-type natriuretisk peptid |
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2014
- 2014-02-20 AU AU2014232030A patent/AU2014232030B2/en active Active
- 2014-02-20 CN CN201480002321.3A patent/CN104619326A/zh active Pending
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- 2014-02-20 WO PCT/JP2014/054023 patent/WO2014141847A1/ja active Application Filing
- 2014-02-20 KR KR1020157005267A patent/KR20150124941A/ko not_active Application Discontinuation
- 2014-02-20 MX MX2015002959A patent/MX2015002959A/es unknown
- 2014-02-20 US US14/426,850 patent/US20150216860A1/en not_active Abandoned
- 2014-02-20 JP JP2015505352A patent/JP6232630B2/ja active Active
- 2014-02-20 EP EP14763917.3A patent/EP2985024A4/en active Pending
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JPH08239327A (ja) * | 1995-03-03 | 1996-09-17 | Taisho Pharmaceut Co Ltd | 慢性骨格筋疼痛の予防又は治療剤 |
US7291461B2 (en) * | 2002-06-21 | 2007-11-06 | Ptc Therapeutics, Inc. | Methods for identifying small molecules that modulate premature translation termination and nonsense mRNA decay |
JP2008533111A (ja) * | 2005-03-16 | 2008-08-21 | サノフイ−アベンテイス | 新規イミダゾ[1,5−a]ピリジン誘導体、該誘導体を調製する方法及び該誘導体を含有する医薬組成物 |
WO2007061130A1 (ja) * | 2005-11-22 | 2007-05-31 | Eisai R & D Management Co., Ltd. | 多発性骨髄腫に対する抗腫瘍剤 |
JP2009520768A (ja) * | 2005-12-21 | 2009-05-28 | ノバルティス アクチエンゲゼルシャフト | Fgf阻害剤であるピリミジニルアリールウレア誘導体 |
WO2011150859A1 (en) * | 2010-06-04 | 2011-12-08 | Comprehensive Drug Enterprises Ltd | Oral meclizine aqueous formulations with taste flavoring agent |
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CN104619326A (zh) | 2015-05-13 |
JP6232630B2 (ja) | 2017-11-22 |
WO2014141847A1 (ja) | 2014-09-18 |
CA2882881A1 (en) | 2014-09-18 |
KR20150124941A (ko) | 2015-11-06 |
US20150216860A1 (en) | 2015-08-06 |
EP2985024A4 (en) | 2016-09-14 |
AU2014232030B2 (en) | 2016-05-26 |
MX2015002959A (es) | 2015-06-05 |
AU2014232030A1 (en) | 2015-03-19 |
EP2985024A1 (en) | 2016-02-17 |
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