JP5094395B2 - Eph受容体を調節することによる神経系内のグリオーシス、グリア瘢痕、炎症、または軸索成長阻害の処置 - Google Patents
Eph受容体を調節することによる神経系内のグリオーシス、グリア瘢痕、炎症、または軸索成長阻害の処置 Download PDFInfo
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Description
本発明は、神経系の障害、特に中枢神経系内のグリオーシス反応および/または炎症反応に関連する障害の治療法と、そのために有用な治療薬に関する。特に、本発明は、神経系への疾患または損傷の間および/または後に起こる、Eph受容体仲介性グリオーシスおよび/もしくはグリア瘢痕および/もしくは炎症および/もしくはEph受容体仲介性の軸索成長阻害を防止する、またはその量を低減させる方法を含む。本発明は、Eph受容体仲介性シグナル伝達を調節する治療薬の同定も促進する。本発明の方法および治療薬は、特に、脳または脊髄への生理的、病理的または外傷による損傷によって誘導される麻痺を含む、一連の神経系の疾患、状態および損傷を治療するために有用である。
本明細書中のいかなる先行技術への参照も、この先行技術が任意の国の共通する一般的知識の一部をなすとの自認または示唆の任意の形であるわけではなく、またそのように理解されるべきではない。
本明細書を通して、文脈からそうではないことが要求されない限り、「含む(comprise)」なる用語や、「含む(comprises)」および「含むこと(comprising)」などの変形は、述べられた整数もしくは段階、または整数もしくは段階群の包含を意味するが、任意の他の整数もしくは段階、または整数もしくは段階群の除外を意味するものではないことが理解されると思われる。
本発明は、疾患または損傷後の中枢神経系内のグリア瘢痕形成はEph受容体、特にEph仲介性シグナル伝達によって仲介されという確認に部分的に基づいている。グリア瘢痕形成はEph受容体によって調節されるとの判断により、疾患もしくは損傷の間またはそれによって生じるものなどの神経系の障害を治療する方法の開発、およびそのために有用な治療薬の開発が促進される。
材料および方法
下記の材料および方法を以下の実施例において用いる。
月齢3〜12ヶ月で以前に記載されたとおり(Coonan et al., J Comp Neurol 436:248-262, 2001)に維持した成獣EphA4-/-およびC57BL/6マウスを本試験で用いた。
マウスをケタミンおよびキシラジンの混合物(それぞれ100mg/kgおよび16mg/kg)で麻酔した。脊髄を椎弓切除術により曝露し、腰膨大のレベルに対応するT12〜L1レベルで2〜3の椎弓を切除した。T12で脊髄左半側切断を細い角膜刃を用いて行い(同じ場所を二回切り、完全切断を確認した)、重なる筋肉および皮膚を縫合した。半側切断を野生型44匹およびEphA4-/-マウス37匹で行った。これらのうち、野生型28匹およびEphA4-/-マウス19匹を用いて免疫組織化学検査を行った。残りのマウスは行動を評価し、続いて軸索トレーシングにより再生の程度を調べた。
脊髄損傷の5週間後、テトラメチルローダミンデキストラン(「Fluoro-Ruby」、分子量10,000kD)を脊髄に損傷と同側の頸膨大のレベルで、ハミルトンシリンジに連結したガラスピペットから注入した。さらに7日間の生存期間の後、マウスに4%パラホルムアルデヒドを灌流した。凍結ミクロトーム上で脊髄の縦の連続切片を50μmで切断し、切片をゼラチン化スライドに固定し、蛍光および共焦点顕微鏡を用いて検査した。
傷害下の腰髄を腰椎下部椎弓切除術により曝露した。注射により損傷された軸索のニューロン細胞体を標識するFast Blue(2%w/v、注入一回あたり0.3μl;EMS-POLYLOY GmBH,Grobβ-Umstadt, Germany)を、傷害部位の同側の脊髄に、ハミルトンシリンジに連結したガラスマイクロピペットで注入した。5日間の生存期間の後、マウスにPBS中の4%パラホルムアルデヒドを灌流した。脳および脊髄を摘出し、固定液中20%スクロース中で24時間後固定した後、凍結ミクロトーム上、冠/横断面で50μmで連続切断した。処置した脊髄縦切片において一側性の注入部位を確認したことから、注入は成功したと考えられた。コンピューター接続デジタル化システム(MD3顕微鏡ディジタイザーおよびMD-プロットソフトウェア;Minnesota Datametrics Corporation, MN, USA)を用い、一連の切片4枚毎に標識細胞の位置をマッピングすることにより、標識ニューロンの定性的および定量的比較を行った。
歩幅:半側切断の前後に、マウスの後ろ足に非毒性インクを塗布し、ブロッティング紙上のトンネル内に置くことにより足形を取った(野生型n=7、EphA4-/- n=9)。歩幅を、複数の連続する足跡の測定によりもとめ、結果を各マウスの基準時歩幅のパーセンテージとして表した。
ウサギ抗-GFAP(1:500、Dako)、マウス抗-CSPG(1:200、Sigma)およびウサギ抗-EphA4を用いた標準免疫組織化学法を行った。ウサギ抗-EphA4抗体(発明者らから入手可能)を、標準法(Cooper and Paterson, Current protocols in molecular biology, eds Ausubel et al. 11.12.11-11.12.19, John Wiley & Sons, New York, 2000)を用いてEphA4の細胞内SAMドメイン(Genbankアクセッション番号NM007936)のアミノ酸938〜953に対応するペプチドに対して調製した。肥大性星状細胞の数、ならびにGFAP-発現星状細胞の総数を、連続する縦8μm切片3つ毎に、傷害部位およびその2.5mm近位の0.25mm2格子内で計数した。肥大性星状細胞は大きい細胞体と複数の厚く長い突起を有する、強く染色されたGFAP-陽性細胞と定義された。非肥大性星状細胞はGFAPに対して染色強度が低く、小さい細胞体と薄く、複雑でない突起を有していた。肥大性星状細胞は非肥大性星状細胞のサイズの二倍よりも大きかった。
精製した星状細胞およびニューロン培養物を、以前に記載されたとおり(Turnley et al., Nat Neurosci 5:1155-1162, 2002)に調製した。神経突起の長さを分析するために、E16皮質ニューロンを、野生型もしくはEphA4-/-星状細胞単層を含む、またはポリーDL-オルニチン/ラミニンコーティングされたチャンバースライド(Falcon、USA)中5,000/ウェルで播種した。いくつかの実験において、星状細胞を単量体エフリンA5-Fc(0.15、1.5、10μg/ml)または複合エフリンA5-Fc(1.5μg/ml、添加前に0.15μg/ml抗ヒトIgG(Vector)と室温で30分間複合)で1時間前処理した。22時間後、細胞を固定し、神経突起マーカーβIII-チューブリン(1:2000、Promega)について免疫染色した。神経突起の長さを、以前(Turnley et al., Neuroreport 9:1987-1990, 1998)と同様に画像分析を用いて測定した。神経突起の長さの平均における差の有意性をスチューデントt検定を用いて解析した。
細胞を溶解し、試料を全タンパク質レベルの分析のために取っておいた。溶解産物の残りはEphA4またはRho活性化分析における免疫沈降のために用いた。EphA4活性化は、抗ホスホチロシン(Cell Signaling)を用いたリン酸化タンパク質の免疫沈降と、続くウェスタン転写およびウサギ抗EphA4抗体(Dr. D. Wilkinson, National Institute for Medical Research, Londonの厚意により提供を受けた)を用いた活性化または全EphA4の検出により評価した。Rho活性化アッセイは、Rhotekin RBDアッセイを製造者(Upstate、USA)の指示に従い用いて行った。全EphA4およびβ-アクチン発現レベルを、非傷害および傷害から7日後の脊髄で、前述のウサギ抗EphA4抗体およびマウス抗β-アクチン抗体(Sigma)を用いたウェスタン分析により評価した。濃度測定をNIH Imageソフトウェアを用いたオートラジオグラフで実施し、EphA4バンドの相対レベルをもとめ、β-アクチンレベルに標準化した。
臭化[3-(4,5-ジメチルチアゾル-2-イル)-2,5-ジフェニル]テトラゾリウム(MTT)アッセイは、生存細胞中のミトコンドリア活性を測定するもので、増殖アッセイとしてよく用いられる(Mosmann, J Immunol Methods 65:55-63, 1983)。生存細胞はテトラゾリウム環を暗青色のホルマザン結晶に変換し、これは光学密度(O.D.)を読み取ることにより定量することができる;O.D.の増大は経時的な細胞数の増加に相関している。野生型およびEphA4-/-星状細胞を、96穴プレート(Falcon)で、10%FCSを補足したDMEM中、LIF(1000U/ml)またはIFN-γ(100U/ml)いずれかの存在下、または非存在下、3×103細胞/ウェルで播種した。MTTアッセイを播種の2、24、48および72時間後に実施した。MTT(0.25mg/ml)を各時点の細胞と共に37℃で2時間インキュベートし、次いで細胞を等量の酸性イソプロパノール(無水イソプロパノール中0.04M HCL)で溶解し、ホルマザン生成物のO.D.を550〜650nmで測定した。
PBS/エフリンA5-Fc(0.687mg/注射)またはPBS単独の注射を、手術後2時間で開始し、次いで24時間毎に2週間までI.P.で行った。
傷害軸索のトレーシングは6週間までに大規模な再生を示す
EphA4-/-マウスはいくらかの発生皮質脊髄路異常を有し、一部の軸索は早期停止するか、または中線を異常に交差するため(Dottori et al., Proc Natl Acad Sci USA 95:13248-13253, 1998;Coonan et al., J Comp Neurol 436:248-262, 2001)、標準の皮質脊髄路トレーシング技術の使用は不可能である。加えて、発明者らは他の軸索路におけるEphA4欠失の影響に関する仮説を立てようと考えなかった。したがって、発明者らは順行性トレーシング技術の利用を選択し、それによりトレーサーを腰の傷害部位よりもずっと上部の頸髄に注入した。これにより、個々の軸索の全般的再生を評価することが可能となった。非傷害野生型およびEphA4-/-マウスでこの技術を用いることにより、注入部位と同側の下行軸索経路の同等の標識が見られたが、注入部位と反対側では標識は見られなかった。
EphA4-/-マウスの機能回復
EphA4-/-マウスで観察された軸索再生は機能的相関も有していた。マウスを、まず脊髄半側切断の前および24時間から4週間後に歩幅を測定することにより(Bregman et al., Nature 378:498-501, 1995)、行動評価した。24時間の時点で、EphA4-/-および野生型マウスはいずれも最小の機能を示した。EphA4-/-マウスは3週間以内にその基準時の歩幅の100%を回復したが、野生型マウスは70%の回復しか示さず(図3d)、その後も改善しなかった。加えて、半側切断の1ヶ月後、同側の後足握力(図3e)および格子上を歩く能力(図3f)はEphA4-/-マウスでは野生型に比べて劇的に改善した。これらの機能は傷害後3ヶ月まで改善し続けた。非傷害EphA4-/-マウスおよび野生型マウスはいずれもこれらの試験で最高の点数を達成した。
EphA4-/-マウスにおける星状細胞グリオーシスの欠損
半側切断EphA4-/-脊髄の著しい特徴は、GFAP発現により評価して、野生型に比べ星状細胞グリオーシスが実質的にないことであった(図4a、b、d、e)。第7日の時点で、野生型傷害部位のGFAP-陽性星状細胞の大多数(90.4%)は肥大性で、GFAPについて非常に強く染色されたが、EphA4-/-星状細胞では7.4%だけが肥大性であった(図4g)。全体に見て、GFAP陽性細胞の総数は傷害後の最初の7日間を通してEphA4-/-半側切断で少なく、これは傷害部位の近位で著しい(図4h)。非傷害例において、EphA4-/-および野生型マウス間で星状細胞数に差はなかった(EphA4-/-の825.6±98.1/mm2に比べて野生型836.8±108.3/mm2)。グリア反応がないことで、グリア瘢痕の成分であるCSPGの免疫染色により評価して、EphA4-/-マウスでは傷害の6週間後にグリア瘢痕のサイズの著しい低下が見られた(図4c、f)。
星状細胞上のEphA4発現は神経突起増殖を阻害する
星状細胞上のEphA4発現を、これがインビトロで皮質ニューロンの神経突起増殖を阻害するかどうかについて調べた。E16皮質ニューロンを野生型またはEphA4-/-星状細胞いずれかの単層上に播種し、22時間後に最も長い神経突起の長さを測定した。これにより、野生型星状細胞に比べてEphA4-/-星状細胞上で増殖の2〜3倍の増大が明らかとなった(図5e〜g)。ニューロンをEphA4を形質移入された293T細胞上で増殖させた場合にも同様の結果が得られた(非形質移入293T細胞上の神経突起の長さは80.4±3.3μmであったのに比べて、EphA4を形質移入した細胞上では30.2±1.9μm)ため、この効果は星状細胞上のEphA4の発現に直接起因すると考えられた。野生型およびEphA4-/-星状細胞の両方における、野生型ニューロンに比べてEphA4-/-ニューロンの神経突起増殖増大(図5g)は、以前に示唆されているとおり(Wahl et al., J Cell Biol 149:263-270、2000;Kullander et al., Genes Dev 15:877-888, 2001)ニューロン上で発現されたEphA4も神経突起増殖を阻害し、EphA4-/-マウスで観察される再生に寄与していることを示唆している。星状細胞上での神経突起増殖の阻害は、星状細胞単層においてEphA4に強く結合する、単量体エフリンA5-Fcの添加により用量依存的様式で強力に阻止されたが、ラミニンコーティングしたガラススライド上で増殖したニューロンには何の影響も無かった(図5h)。反対に、以前に記載されたとおり(Wahl et al., J Cell Biol 149:263-270, 2000;Kullander et al., Genes Dev 15:877-888, 2001)、複合エフリンA5-Fcの添加はガラススライド上で神経突起増殖を阻害し、星状細胞上で増殖をさらに阻害した(図5h)。これは、星状細胞上のEphA4の阻止は神経突起増殖を増強するが、ニューロン上ではそのような効果は見られず、一方でニューロンおよび星状細胞両方におけるEphA4の活性化は神経突起増殖を阻害することを示している。これらの結果はいずれも、リガンドによるEphA4の活性化が神経突起阻害のメカニズムであることを直接示すものである。インビボで、星状細胞上のEphA4発現に対する神経突起反応の活性化物質の可能性があるものはエフリンB3で、これはシグナルを変換することが示されており(Palmer et al., Mol Cell 9:725-737, 2002)、脊髄における再生中の軸索によって発現された。
Rho活性化および増殖はEphA4-/-星状細胞において低減させる
以前の試験が、グリオーシスはインターフェロン-γ(IFNγ)および白血病阻害因子(LIF)を含む炎症サイトカインによって仲介されると示している(Yong et al., Proc Natl Acad Sci USA 88:7016-7020, 1991;Balasingam et al., J Neurosci 14:846-856, 1994;Sugiura et al., Eur J Neurosci 12:457-466, 2000)ことを考慮して、発明者らはこれらのサイトカインが星状細胞上のEphA4のアップレギュレーションにおいて役割を果たしているかどうかを調べた。IFNγおよびLIFはEphA4発現をそれぞれ56%および69%アップレギュレートしたが、インターロイキン-1(Il-1)および腫瘍壊死因子-α(TNFα)は効果がなかった(図6a)。EphA4発現が星状細胞反応につながりうる下流活性化を伴うかどうかの疑問に直接取り組むため、発明者らはEphA4がリン酸化されるかどうかを調べた。IFNγおよびLIFはいずれも、可溶性多量体EphA4リガンドであるエフリンA5-Fcの添加と同様の様式で、EphA4リン酸化を2倍アップレギュレートした(図6a)。加えて、これは、Eph受容体シグナル伝達の下流の細胞骨格変化の主な調節物質である、低分子GTPアーゼ、Rho(Hall, Science 279:509-514, 1998)の活性化における著しい増加を引き起こした(Wahl et al., J Cell Biol 149:263-270, 2000;Shamah et al., Cell 105:233-244, 2001)。Rho活性化増大は傷害部位から摘出した野生型脊髄組織(図6b)および培養星状細胞(図6c)の両方で起こったが、傷害EphA4-/-動物から摘出した細胞または組織を用いて、そのような反応は観察されなかった。星状細胞、ならびにニューロンおよび乏突起膠細胞におけるRhoの活性化も、損傷後の脊髄において最近報告されている(Dubreuil et al., J Cell Biol 162:233-243, 2003)。
エフリンA5-Fcの注射は軸索再生を増大させる
単量体エフリンA5-FcはインビトロでEphA4の活性化を阻止する。エフリンA5-Fc注射後、脊髄傷害を受けたマウスの星状細胞グリオーシスは、PBS単独を注射したものに比べて、有意に低減する(図7Aおよび7B)。同様に、2週間のエフリンA5-Fc注射も損傷脊髄におけるEphA4アップレギュレーションを阻害する(図8)。傷害から2週間後のマウスの脊髄で軸索再生を調べる場合、PBS単独(図10)に比べてエフリンA5-Fc注射後(図9)に、傷害部位付近の有意な側枝出芽および再生が起こる。この再生はSCIおよびエフリンA5-Fc注射を受けたマウスの格子歩行およびよじ登りにおける有意な改善に反映される(図11)。SCIの6週間後、傷害部位をまたがる有意な軸索再生がエフリンA5-Fcを注射されたマウスで観察される(図12)。
Claims (3)
- 対象の神経系内のグリオーシスおよび/もしくは軸索成長阻害を防止する、またはその量を低減させるための、エフリンA4受容体アンタゴニストを含む薬剤であって、前記エフリンA4受容体アンタゴニストがエフリンA5-Fcである、前記薬剤。
- 対象がヒトである、請求項1記載の薬剤。
- 請求項1または2記載の薬剤と一つまたは複数の薬学的に許容される担体および/または希釈剤および/または賦形剤とを含む薬学的組成物。
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AUPP674898A0 (en) * | 1998-10-27 | 1998-11-19 | Walter And Eliza Hall Institute Of Medical Research, The | A method of treatment |
ES2242437T3 (es) * | 1998-11-20 | 2005-11-01 | Genentech, Inc. | Utilizaciones de agonistas y antagonistas del receptor eph para el tratamiento de trastornos vasculares. |
EP1553963A4 (en) * | 2002-09-24 | 2006-05-03 | Burnham Inst | NOVEL AGENTS MODULATING EPH RECEPTOR ACTIVITY |
AU2003287424A1 (en) * | 2002-11-01 | 2004-06-07 | Case Western Reserve University | Methods of inhibiting glial scar formation |
WO2005056766A2 (en) * | 2003-12-04 | 2005-06-23 | Medimmune, Inc. | TARGETED DRUG DELIVERY USING EphA2 OR Eph4 BINDING MOIETIES |
CA2579352A1 (en) * | 2004-09-08 | 2006-03-16 | The University Of Queensland | Treating gliosis, glial scarring, inflammation or inhibition of axonal growth in the nervous system by modulating eph receptor |
-
2005
- 2005-09-08 CA CA002579352A patent/CA2579352A1/en not_active Abandoned
- 2005-09-08 US US11/662,355 patent/US20080254023A1/en not_active Abandoned
- 2005-09-08 EP EP05778955A patent/EP1793854A4/en not_active Withdrawn
- 2005-09-08 NZ NZ553273A patent/NZ553273A/en not_active IP Right Cessation
- 2005-09-08 JP JP2007530543A patent/JP5094395B2/ja not_active Expired - Fee Related
- 2005-09-08 WO PCT/AU2005/001363 patent/WO2006026820A1/en active Application Filing
-
2012
- 2012-02-15 JP JP2012030227A patent/JP2012136529A/ja not_active Withdrawn
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012136529A (ja) * | 2004-09-08 | 2012-07-19 | Univ Of Queensland | Eph受容体を調節することによる神経系内のグリオーシス、グリア瘢痕、炎症、または軸索成長阻害の処置 |
Also Published As
Publication number | Publication date |
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WO2006026820A9 (en) | 2007-04-05 |
EP1793854A1 (en) | 2007-06-13 |
JP2012136529A (ja) | 2012-07-19 |
NZ553273A (en) | 2009-11-27 |
CA2579352A1 (en) | 2006-03-16 |
EP1793854A4 (en) | 2008-01-02 |
US20080254023A1 (en) | 2008-10-16 |
JP2008512394A (ja) | 2008-04-24 |
WO2006026820A1 (en) | 2006-03-16 |
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