JPWO2017022628A1 - 上皮疾患に対する治療及び/又は予防有効性を評価する方法、上皮疾患治療剤のスクリーニング方法、及び上皮疾患治療剤 - Google Patents
上皮疾患に対する治療及び/又は予防有効性を評価する方法、上皮疾患治療剤のスクリーニング方法、及び上皮疾患治療剤 Download PDFInfo
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Abstract
Description
〔1〕細胞及び/又はその培養上清を含む製剤において、サイクロフィリンBを指標に、上記製剤の、上皮疾患に対する治療及び/又は予防有効性を評価する方法。
〔2〕上記上皮疾患が、上皮間葉転換が関与している疾患である、〔1〕記載の方法。
〔3〕上記上皮疾患が、眼部、肝臓、肺、腎臓、消化管、気道又は腹膜における疾患である、〔1〕又は〔2〕記載の方法。
〔4〕上記上皮疾患が、線維症である、〔1〕から〔3〕のいずれか記載の方法。
〔5〕上記上皮疾患が、角膜疾患、網膜疾患又は表皮疾患である、〔1〕から〔4〕のいずれか記載の方法。
〔6〕上記上皮疾患が、翼状片、瘢痕、EBウイルス角膜炎、角膜上皮幹細胞疲弊症、硝子体網膜症、又は強皮症である、〔5〕記載の方法。
〔7〕上記上皮疾患が、癌である、〔1〕又は〔2〕記載の方法。
〔8〕上記細胞が、間葉系幹細胞である、〔1〕から〔7〕のいずれか記載の方法。
〔9〕上記間葉系幹細胞が、脂肪由来間葉系幹細胞又は臍帯由来間葉系幹細胞である、〔8〕記載の方法。
〔10〕細胞におけるサイクロフィリンBの発現量、又は細胞培養上清中のサイクロフィリンBの含有量を測定する工程を含む、上記細胞又はその培養上清の、上皮疾患に対する治療及び/又は予防有効性を評価する方法。
〔11〕得られたサイクロフィリンB量を、基準となるサイクロフィリンB量と比較する工程をさらに含む、〔10〕記載の方法。
〔12〕〔1〕から〔11〕のいずれか記載の方法を用いる、上皮疾患治療剤のスクリーニング方法。
〔13〕〔12〕記載のスクリーニング方法により選択された上皮疾患治療剤であって、間葉系幹細胞又はその培養上清を含むことを特徴とする、上皮疾患治療剤。
〔14〕上記上皮疾患が、上皮間葉転換が関与している疾患である、〔13〕記載の上皮疾患治療剤。
〔15〕上記上皮疾患が、眼部、肝臓、肺、腎臓、消化管、気道又は腹膜における疾患である、〔13〕又は〔14〕記載の上皮疾患治療剤。
〔16〕上記上皮疾患が、線維症である、〔13〕から〔15〕のいずれか記載の上皮疾患治療剤。
〔17〕上記上皮疾患が、角膜疾患、網膜疾患又は表皮疾患である、〔13〕から〔16〕のいずれか記載の上皮疾患治療剤。
〔18〕上記上皮疾患が、翼状片、瘢痕、EBウイルス角膜炎、角膜上皮幹細胞疲弊症、硝子体網膜症、又は強皮症である、〔17〕記載の上皮疾患治療剤。
〔19〕上記上皮疾患が、癌である、〔13〕記載の上皮疾患治療剤。
本発明の評価方法は、細胞及び/又はその培養上清中のサイクロフィリンBを指標に、上記細胞又はその培養上清の、上皮疾患に対する治療及び/又は予防有効性を評価できる方法である。以下に、本発明の評価方法を詳細に説明する。本発明の評価方法は、細胞におけるサイクロフィリンBの発現量、又は細胞培養上清中のサイクロフィリンBの含有量を測定する工程(以下、「測定工程」ともいう)を含む。また、得られたサイクロフィリンB量を、基準となるサイクロフィリンB量と比較する工程(以下、「比較工程」ともいう)を含むことが好ましい。さらに、細胞又は細胞培養上清の上皮疾患に対する治療・予防効果を確認するために上皮間葉転換(EMT)抑制活性を測定する工程(以下、「確認工程」ともいう)を含むことがより好ましい。なお、上記サイクロフィリンB量とは、細胞におけるサイクロフィリンBの発現量及び/又は細胞培養上清中のサイクロフィリンBの含有量をいう。
本発明の上皮疾患治療剤のスクリーニング方法は、本発明の上記評価方法を用いる。本発明の評価方法により、評価対象の細胞又は細胞培養上清の上皮疾患に対する治療・予防有効性を評価した後、上皮疾患治療剤として次の開発段階に進めるか否かを判断する方法である。本発明のスクリーニング方法によると、上皮疾患に対する治療・予防効果を有する細胞又は細胞培養上清を簡便に選択できるため、新規の上皮疾患治療剤の探索研究において、有効に活用することができる。
本発明は、本発明のスクリーニング方法により選択された上皮疾患治療剤も含む。
本発明の上皮疾患治療剤が含む細胞又は細胞培養上清における「細胞」としては、動物細胞であってもよいし、植物細胞であってもよいが、細胞を含む医薬組成物を使用する対象と同種由来の細胞であることが好ましい。特に、ヒトの上皮疾患に対する治療、予防のために使用する場合には、ヒトの細胞であることが好ましい。このような細胞としては、本発明者により培養上清に上皮疾患に対する効果(上皮間葉転換の抑制効果)が確認された間葉系幹細胞が好ましい。上記間葉系幹細胞としては、例えば、骨髄、脂肪、筋肉、神経、皮膚、羊膜、胎盤、絨毛膜、脱落膜又は臍帯由来の間葉系幹細胞が挙げられるが、これらのうち、サイクロフィリンBの分泌量が多い細胞である臍帯由来間葉系幹細胞、脂肪由来間葉系幹細胞、骨髄由来間葉系幹細胞が好ましく、臍帯由来間葉系幹細胞、脂肪由来間葉系幹細胞がより好ましい。
本発明の上皮疾患治療剤は、本発明のスクリーニング方法により選択された細胞又は細胞培養上清と、その他の成分を常法により混合して製造することができる。
本発明の上皮疾患治療剤は、線維症及び線維症関連疾患、並びに癌及び癌関連疾患等の上皮疾患に対して好適に用いられる。なかでも、EMTが関与する疾患、さらには、眼部、肝臓、肺、腎臓、消化管、気道、腹膜等においてEMTが関与する疾患に対して好ましく用いられる。
間葉系幹細胞は脂肪由来幹細胞(AD−MSC, Lonza)、骨髄由来幹細胞(BM−MSC, Lonza)、臍帯由来幹細胞(UC−MSC,Lifeline Cell Technology)を使用し、培養液はヒト間葉系幹細胞専用完全合成培地キット(MSC−GMCD,Lonza)を用いた。線維芽細胞は、ヒト皮膚線維芽細胞(NHDF,クラボウ)を使用し、培養液は10% FBS含有 DMEM(Lifetechnologies)を用いた。それぞれの細胞を培養液で培養した後、MSC−GMCD培地に交換し、さらに2−5日間培養した後、上清を300xgで遠心処理後、上清を評価用の培養上清として取得した。各細胞の培養上清を総タンパク量が25μg(陽性細胞のHepG2 cell lysateは12.5μg)となるように調製し、5%β−mercaptoethanol を含有した4 x NuPAGE LDS Sample Buffer(Bio−Rad)を総量の1/4量加え、70℃で10分間インキュベートし、サンプルとした。SDS−PAGEは4−12%のNuPAGE Novex Bis−Trisゲル(invitrogen)を用いて電気泳動した。iBlotシステム(invitrogen)を用いてPVDFメンブレンに転写した後、5% skim milk/PBS中で室温にて1時間ブロッキングした。0.05% Tween20含有TBS(TBS−T)で5分間3回洗浄したメンブレンを一次抗体に室温で1〜4時間または4℃で一晩反応させ、TBS−Tで5分間3回洗浄した後、二次抗体に室温で45分間反応させた。一次抗体には、抗Cyclophilin B抗体(#ab16045, abcam)(1,200倍希釈)を使用した。二次抗体には、HRP標識抗ウサギIgG抗体(10,000倍希釈)を使用した.抗体はいずれもTBSで希釈して使用した。発光にはECL prime(GE healthcare Bio−Sciences)を使用し、ChemiDoc XRS(Bio−Rad) にて検出した。結果を図1に示す。
また、両方の結果を表1に合わせて示した。
AD−MSC、AD−MSC2:脂肪由来間葉系幹細胞
BM−MSC:骨髄由来間葉系幹細胞
UC−MSC:臍帯由来間葉系幹細胞
NHDF:皮膚線維芽細胞
サイクロフィリンB含有培養上清の表皮角化細胞(NHEK)のEMT抑制効果を次のように調べた。すなわち、24 well plate(BD Falcon)に表皮角化細胞(NHEK)を2.0×104 cells/well (1.06×104 cells/cm2)の細胞密度で播種し、37℃、5% CO2条件下にて培養し、24時間後、10 ng/mL濃度のTGF−β1およびTNF−αを添加した培養液を加え、さらに3日間培養を行った後、サイクロフィリンBを含有するAD−MSCの培養上清(すべてMSC−GMCD培地)を培地全体の半量となるように添加し、さらに3日間培養を行った後、RNeasy kit(QIAGEN)を用いてRNAを抽出・精製し、SuperScript(登録商標) III First−Strand Synthesis SuperMix for qRT−PCR (Invitrogen)を用いてcDNAを合成した。合成したcDNAを用いてTaqmanアッセイ(Life technologies)により遺伝子発現解析を行った。その結果を図3に示す。
網膜色素上皮細胞株(ARPE−19)のTGF−β1添加によるEMT様遺伝子変動を、以下のように確認した。すなわち、24 well plate(BD Falcon)に網膜色素上皮細胞株(ARPE−19)を2.5×104 cells/cm2の細胞密度で播種し、37℃、5% CO2条件下にて、5または10ng/mL濃度のTGF−β1を含む培養液(10%FBS含有DMEM/F12)で4日間培養を行った後、QIAzol Lysis Reagent(QIAGEN)を用いてRNAを抽出・精製し、SuperScript(登録商標) III First−Strand Synthesis SuperMix for qRT−PCR (Invitrogen)を用いてcDNAを合成した。合成したcDNAを用いてTaqmanアッセイ(Life technologies)により遺伝子発現解析を行った。その結果を図4に示す。
Claims (19)
- 細胞及び/又はその培養上清を含む製剤において、サイクロフィリンBを指標に、上記製剤の、上皮疾患に対する治療及び/又は予防有効性を評価する方法。
- 上記上皮疾患が、上皮間葉転換が関与している疾患である、請求項1記載の方法。
- 上記上皮疾患が、眼部、肝臓、肺、腎臓、消化管、気道又は腹膜における疾患である、請求項1又は2記載の方法。
- 上記上皮疾患が、線維症である、請求項1から3のいずれか1項記載の方法。
- 上記上皮疾患が、角膜疾患、網膜疾患又は表皮疾患である、請求項1から4のいずれか1項記載の方法。
- 上記上皮疾患が、翼状片、瘢痕、EBウイルス角膜炎、角膜上皮幹細胞疲弊症、硝子体網膜症、又は強皮症である、請求項5記載の方法。
- 上記上皮疾患が、癌である、請求項1又は2記載の方法。
- 上記細胞が、間葉系幹細胞である、請求項1から7のいずれか1項記載の方法。
- 上記間葉系幹細胞が、脂肪由来間葉系幹細胞又は臍帯由来間葉系幹細胞である、請求項8記載の方法。
- 細胞におけるサイクロフィリンBの発現量、又は細胞培養上清中のサイクロフィリンBの含有量を測定する工程
を含む、上記細胞又は細胞培養上清の、上皮疾患に対する治療及び/又は予防有効性を評価する方法。 - 得られたサイクロフィリンB量を、基準となるサイクロフィリンB量と比較する工程
をさらに含む、請求項10記載の方法。 - 請求項1から11のいずれか1項記載の方法を用いる、上皮疾患治療剤のスクリーニング方法。
- 請求項12記載のスクリーニング方法により選択された上皮疾患治療剤であって、間葉系幹細胞又はその培養上清を含むことを特徴とする、上皮疾患治療剤。
- 上記上皮疾患が、上皮間葉転換が関与している疾患である、請求項13記載の上皮疾患治療剤。
- 上記上皮疾患が、眼部、肝臓、肺、腎臓、消化管、気道又は腹膜における疾患である、請求項13又は14記載の上皮疾患治療剤。
- 上記上皮疾患が、線維症である、請求項13から15のいずれか1項記載の上皮疾患治療剤。
- 上記上皮疾患が、角膜疾患、網膜疾患又は表皮疾患である、請求項13から16のいずれか1項記載の上皮疾患治療剤。
- 上記上皮疾患が、翼状片、瘢痕、EBウイルス角膜炎、角膜上皮幹細胞疲弊症、硝子体網膜症、又は強皮症である、請求項17項記載の上皮疾患治療剤。
- 上記上皮疾患が、癌である、請求項13記載の上皮疾患治療剤。
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