JP6620129B2 - 新規な組換えエキソソーム及びその用途 - Google Patents
新規な組換えエキソソーム及びその用途 Download PDFInfo
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- JP6620129B2 JP6620129B2 JP2017151429A JP2017151429A JP6620129B2 JP 6620129 B2 JP6620129 B2 JP 6620129B2 JP 2017151429 A JP2017151429 A JP 2017151429A JP 2017151429 A JP2017151429 A JP 2017151429A JP 6620129 B2 JP6620129 B2 JP 6620129B2
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本明細書で使われる用語“グルコース輸送体(glucose transporter)”は、ブドウ糖を細胞膜に通過させて細胞内に移入させるタンパク質を意味するが、グルコース輸送体は、12個の膜通過螺旋を含む膜タンパク質であって、アミノ末端とカルボキシ末端いずれも細胞質方面に露出されている。グルコース輸送体は、ヒトの場合、現在まで14種が報告されており、アミノ酸配列の相同性によって、GLUT1ないしGLUT4、及びGLUT14が属した系列I(class I)、GLUT5、GLUT7、GLUT9及びGLUT11が属した系列II(class II)、そして、GLUT6、GLUT8、GLUT10、GLUT12、HMIT(H+/myoinositol transporter)が含まれた系列III(class III)が含まれる。
(実施例1:VSV−G及びCD63を含む組換えエキソソームの製造及び標的細胞への導入)
本発明者らは、膜タンパク質をVSV−Gタンパク質を含むエキソソームに含ませた後、エキソソームを標的細胞と接触させて、前記膜タンパク質を標的細胞の細胞膜に伝達することができるという仮説を立て(図1参照)、前記仮説が実際妥当であるか否かを調査するために、蛍光タンパク質であるGFPを膜タンパク質であるCD63と融合させた融合タンパク質をVSV−Gを含むエキソソームに導入させた後、標的細胞との接触以後、蛍光の分布態様を観察した。
(実施例2:VSV−G及びGLUT4を含む組換えエキソソームの製造及び標的細胞への導入)
本発明者らは、前記実施例1の結果から、グルコース輸送体であるGLUT4の標的細胞の細胞膜への特異的な伝達、及びこれを通じて標的細胞及び標的組織でのブドウ糖吸収調節が可能であるか否かを確認しようとした。
(実験例1:エキソソーム融合能の評価)
本発明者らは、前記実施例1から製造された組換えエキソソームに含まれたVSV−Gタンパク質の融合活性によって、膜タンパク質の伝達がなされるかを確認するために、細胞膜脂質組成を模写する人工リポソームと単一エキソソーム粒子の融合効率を分析するために、試験管内の単一小胞体造影分析(single−vesicle imaging analysis)を開発した。具体的に、本発明者らは、エキソソームと人工リポソームとの間の平均融合回数を提供することができる全体内部反射蛍光顕微鏡を用いて蛍光共鳴エネルギー転移(FRET)分析を行った。このために、本発明者らは、リポソームをVSV−Gの細胞進入窓口役割を行うHis標識低密度脂質タンパク質受容体(low−density lipoprotein receptor、LDLR)を結合させるために、1% Ni−ニトリロ三酢酸(nitrologtriacetic acid、NTA)でドーピングした。最近、研究を通じてVSV−Gが偏在細胞表面(universal cell surface)LDLR及び他のLDL系の構成員と結合することによって、VSVの結合及び標的細胞膜への融合を可能にするものと報告されている。前記単一小胞体造影分析で小胞は、供与蛍光団(donor fluorophore、DiI)及び受容蛍光団(acceptor fluorophore、DiD)を有する他の小胞体のうち何れか1つと対を成した(図5A)。図5Aは、本発明の一実施例による前記単一小胞体造影分析を概略的に示す概要図である。FERT効率は、各小胞体の対が平衡状態を成し、対を成していない小胞体が除去された以後に測定し、前記対を成した小胞体から測定されたデータを通じて融合された集団(低FRET)及び完全に脂質混合された集団(高FRET)を区分した。図5Aに示されたように、柔細胞分析器のフローセル(flow cell)でDiD−標識リポソームをPEGコーティングされた表面に固定した後、DiI標識されたエキソソームを添加し、単一エキソソーム−リポソーム複合体を形成させた後、pH5.5の酸性条件で脂質混合を触発させた結果、86%に近い固定された小胞体が脂質混合を形成するなどFRET効率が増加した(図5Bの下端及び図5C)。図5Cで、低FRETは、FRET効率が0.4未満である時を示し、中間FRETは、FRET効率が0.4以上0.65未満である時を示し、高FRETは、FRET効率が0.65以上である場合を示す。一方、中性pHでは、30分間反応後にもリポソーム−エキソソーム融合がほとんど起きなかった(図5Bの上端)。さらに、本発明者らは、LDLRがリポソームとエキソソームとの間の結合を促進させ、これは、VSV−G依存的であることを確認した(図5D及び表1)。図5Dは、結合副集団の分率を示すグラフである。前記結果は、エキソソームの構成成分が安定したエキソソーム結合の達成には十分ではないということを示唆するものである。
前記実施例2の結果から、本発明者らは、本発明の一実施例による組換えエキソソームの処理によって標的細胞のブドウ糖吸収能が増加するかを実験的に調査した。
その結果、図7で示すように、本発明の一実施例による融合性エキソソーム処理細胞では、エキソソーム濃度依存的にブドウ糖吸収率が増加し、アピゲニン処理時には、ブドウ糖吸収率が多少減少したが、20μg/ml処理群の場合、何も処理していない陰性対照群に比べて、さらに高いブドウ糖吸収率を示して、GLUT1の発現阻害にもかかわらず、ブドウ糖吸収効率が増加することが確認され、これは、エキソソームによってGLUT4が標的細胞の細胞膜に伝達されて、GLUT4によってブドウ糖が細胞内に吸収されたためであることを示唆するものである。
(実験例3:生体内ブドウ糖吸収能の評価)
これにより、本発明者らは、本発明の一実施例によるエキソソームを実際動物に投与時に、当該動物のブドウ糖吸収能が改善されるかを確認するための動物実験を行った。
(実験例4:筋肉再生効果の評価)
<4−1:毒素誘発損傷筋肉の再生促進効果>
本発明者らは、前記実施例4の結果から、本発明の一実施例による組換えエキソソームが生体内条件でGLUT4を筋細胞に適切に伝達するということを確認した。実験動物の足の前脛骨筋(tibialis anteror muscle)にCTX(Cardiotoxin)を投与して筋肉損傷を誘導する時、約2〜3週が経過すれば、自然的に治癒になる。本発明者らは、エキソソームによるGLUT4の筋細胞への伝達によって、前記筋肉再生がさらに促進されるか否かを確認しようとした(Moreno H et al.,J.Biol.Chem.,2003,278(42):40557−40564)。具体的に、本発明者らは、Leeらが報告したように、8〜10週齢のC57BL/6雄性マウスの両側前脛骨筋に筋肉毒素である10μMの濃度のcardiotoxin(CTX)50μlを筋肉内注射して、筋肉損傷を誘導した(Lee et al.,Scientific Reports,5:16523,2015)。CTX注入1日目に、融合性エキソソーム及び対照群として非融合性エキソソームをそれぞれ100μgを筋肉内注入した後、2日おきにそれぞれのエキソソームを6回さらに100μgずつ筋肉内投与した(図9A)。
<4−2:筋細胞の融合に及ぼす影響>
本発明者らは、前記実験例4−1の分析に続き、本発明の一実施例によるVSV−G含む融合性エキソソームの筋細胞の融合に及ぼす影響を調査した。
Claims (11)
- 膜にグルコース輸送体タンパク質(GLUT)及び膜融合タンパク質が含まれた組換えエキソソームを有効成分として含む糖尿病の治療のための薬学的組成物。
- 前記グルコース輸送体タンパク質は、GLUT1、GLUT2、GLUT3、GLUT4、GLUT5、GLUT6、GLUT7、GLUT8、GLUT9、GLUT10、GLUT11、GLUT12、HMIT、またはGLUT14である請求項1に記載の薬学的組成物。
- 前記膜融合タンパク質は、VSV−G、HIVのtatタンパク質、HSV−1 gB、EBV gB、トゴトウイルスGタンパク質、またはAcMNPV gp64である請求項1に記載の薬学的組成物。
- 前記グルコース輸送体タンパク質及び膜融合タンパク質が発現されるように形質転換された細胞から収得された請求項1に記載の薬学的組成物。
- 前記組換えエキソソームの内部に1つ以上の他の糖尿病治療剤をさらに含む請求項1に記載の薬学的組成物。
- 前記糖尿病治療剤は、メトホルミン、ブホルミン、フェンホルミン、ロシグリタゾン、ピオグリタゾン、トログリタゾン、トルブタミド、アセトヘキサミド、トラザミド、クロルプロパミド、グリベンクラミド、ミチグリニド、グリピジド、グリブリド、グリメピリド、グリクラジド、グリクロピラミド、グリキドン、レパグリニド、ナテグリニド、ミグリトール、アカルボース、ボグリボース、グルカゴン類似ペプチド−1(GLP−1)またはその誘導体、ビルダグリプチン、シタグリプチン、サキサグリプチン、リナグリプチン、アログリプチン、セプタグリプチンまたはテネグリプチンである請求項5に記載の薬学的組成物。
- 膜にグルコース輸送体タンパク質(GLUT)及び膜融合タンパク質が含まれた組換えエキソソームまたは上記組換えエキソソームの内部に別の糖尿病治療薬が追加された組換えエキソソームを有効成分として含む血糖降下用薬学的組成物。
- 膜にグルコース輸送体タンパク質(GLUT)及び膜融合タンパク質が含まれた組換えエキソソームまたは膜に膜融合タンパク質を含む組換えエキソソームを有効成分として含む筋疾患治療用薬学的組成物。
- 前記膜融合タンパク質は、VSV−G、HIVのtatタンパク質、HSV−1 gB、EBV gB、トゴトウイルスGタンパク質、またはAcMNPV gp64である請求項8に記載の薬学的組成物。
- 前記筋疾患は、線維筋腫、炎症性筋肉病、筋異栄養症、デュシェンヌ型筋異栄養症、ハンチントン病、パーキンソン病、筋肉痛、軟部組織肉腫、リウマチ性多発性筋肉痛、筋肉痙攣、シャルコー・マリー・トゥース病(CMT)、ポンペ病、ファブリー病、コリまたはフォーブズ病、タルイ病、マッカードル病、筋炎、封入体筋炎、シャープ症候群、多発性筋炎、手根管症候群、多発性末梢神経症、脊髄性筋萎縮症(SMA)、ルーゲーリック病(ALS)、炎症性筋肉病、重症筋無力症または筋肉破裂である請求項8に記載の薬学的組成物。
- 膜にグルコース輸送体タンパク質(GLUT)及び膜融合タンパク質が含まれた組換えエキソソームまたは膜に膜融合タンパク質を含む組換えエキソソームを含む筋肉再生促進用組成物。
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