JP7372619B2 - 治療方法 - Google Patents
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- JP7372619B2 JP7372619B2 JP2021099640A JP2021099640A JP7372619B2 JP 7372619 B2 JP7372619 B2 JP 7372619B2 JP 2021099640 A JP2021099640 A JP 2021099640A JP 2021099640 A JP2021099640 A JP 2021099640A JP 7372619 B2 JP7372619 B2 JP 7372619B2
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Description
本出願は、その内容全体が参照によって本明細書に組み入れられる、「治療の方法」と題する2015年6月12日に出願されたオーストラリア仮特許出願番号2015902214及び「治療方法」と題する2016年4月12日に出願されたオーストラリア仮特許出願番号2016901349に由来する優先権に関連するものであり、それを主張する。
本開示は一般に、組織性及びニューロン性の修復、再生及び/又は回復を促すための強化された細胞に基づく治療アプローチによる哺乳動物被験体における治療の方法に関する。哺乳動物被験体の治療に有用な薬物及び薬物の製造方法も本開示によって包含される。
(i)必要に応じて、ドナーを特定することと、
(ii)培養にて上皮細胞によって産生される羊膜エキソソームのプロテオーム及び/又は遺伝子的プロフィールに基づいて特定のドナー又はあるドナーから不死化された羊膜上皮細胞を選択することと、
(iii)選択された不死化羊膜上皮細胞から馴化培地を生成することと、
(iv)馴化培地から羊膜エキソソームを単離することと、
(v)羊膜エキソソームを哺乳動物被験体に全身又は局所投与することとを含む。
(i)必要に応じて、ドナーを特定することと、
(ii)培養にて上皮細胞によって産生される羊膜エキソソームのプロテオーム及び/又は遺伝子的プロフィールに基づいて特定のドナー又はあるドナーから不死化された羊膜上皮細胞を選択することと、
(iii)選択された不死化羊膜上皮細胞から馴化培地を生成することと、
(iv)馴化培地から羊膜エキソソームを単離することと、
(v)羊膜エキソソームをヒト被験体に全身又は局所投与することとを含む。
(i)必要に応じて、ドナーを特定することと、
(ii)エキソソームによって放出される作用物質のプロテオーム及び/又は遺伝子的プロフィールに基づいて特定のドナー又はあるドナーから羊膜エキソソームを選択することと、
(iii)羊膜エキソソームを哺乳動物被験体に全身又は局所投与することとを含む。
(i)必要に応じて、ドナーを特定することと、
(ii)エキソソームによって放出される作用物質のプロテオーム及び/又は遺伝子的プロフィールに基づいて特定のドナー又はあるドナーから羊膜エキソソームを選択することと、
(iii)羊膜エキソソームをヒト被験体に全身又は局所投与することとを含む。
羊膜エキソソームを単離するためにプロトコールを開発する(図1)。これは、羊膜エキソソームの初めての記載であり、その生物活性の検証である。hAECの初代単離物を無血清培地(Ultraculture media,Lonza)で96時間培養したのち、細胞を取り除き、110,000gでの連続超遠心を介したエキソソームの単離のために馴化培地を処理する。在胎期間にかかわらず、100万個のhAEC当たりおよそ1.5~2μgの精製エキソソームが一貫して精製される。アポトーシス小体を混入させることなく、これをバイオリアクター型の培養で規模拡大することができる。
羊膜エキソソームがインビボで機能的であるかどうかを判定した。羊膜エキソソーム1μgのアリコートを出生後4日目のBPDマウスに静脈内注射し、出生後14日目に組織:気腔の比率の評価を行った。羊膜エキソソームは肺胞単純化を元に戻すことにおいて有効だった(図3)。羊膜エキソソームは、BPDマウスにて炎症を解消しながら、肺胞単純化を減らし、内在性幹細胞を動員することによって、それらが肺構造に対する有害な変化を防ぐ又は元に戻す主要な役割を担っている。
データは、羊膜エキソソームがインビトロ及びインビボで免疫調節効果及び再生促進効果を発揮することを示している。修復の間に羊膜エキソソームが細胞のクロストークにどのように影響を与えるのかを理解するために、及びBPDの動物モデルにてhAECの回復効果を総括するのに羊膜エキソソームだけで十分なのかどうかを判定するために、hAECの最適化された用量に対して2つの用量(1μgと10μg)の羊膜エキソソームの効果を比較する。線維芽細胞及び線維芽細胞エキソソームを対照として使用する。
肺を回収し、以前記載された(Noldら.(2013)上記;Tanら.(2015),Stem Cell Res.Ther.6:8)ようにフローサイトメトリー用に処理する。CD45+分画を選別し、表面マーカーと細胞内サイトカインの染色の組み合わせを用いてT細胞(CD3、CD4、CD25、IFNγ、IL-4、IL17A、FoxP3)、マクロファージ(CD11b、F4/80、CD86、MHCII)、好中球(CD11c、Ly6G)、B細胞(B220)及びNK細胞(NK1.1)の数、表現型及び活性化状態に対する変化を評価する。気管支肺胞洗浄液を回収し、以前記載された(Noldら.(2013)上記)ような、Proteome Profiler(R&D Systems)を用いてサイトカインの変化を測定する。
CD45-/CD31-/Sca-1+/EpCam+(Leeら.(2014),Cell,156:440-455)の基準に基づいてフローソーティングによってBASC集団に対する変化を測定する。これは、上記の免疫細胞の試験に由来する細胞のCD45+分画を使用する。AT2はCD31-/Sca1-/自己蛍光高のフローソーティングに基づいて選別される。単一細胞デジタルPCR(Fluidigm,qdPCR 37K)を用いて転写プロフィールの差異を判定する。細胞溶解、RNAの単離、事前増幅及びcDNAへの変換が発生するであろう96穴のマイクロ流体プレート(C1単一細胞Autoprep System,Fluidigm)にてフローソーティングした単一細胞を捕捉する。次いで試料をデジタルPCR用のマイクロ流体カードに負荷する。SINGuLAR v2.0解析ツールセットを用いてデータを解析する。BASC及びAT2の微小環境活性化経路が十分には記載されていないので、カスタマイズされた48:48deltaGeneアッセイにより、最近記載されたBMP1/NFATc1/トロンボスポンジン-1軸(Leeら.(2014)上記)を含む幹細胞の多能性、活性化、動員及び分化をカバーする。
組織:気腔の比率を測定する定量的画像解析を行って実験群すべてにわたって肺胞の単純化の程度を判定する。
終末細気管支でのBASCについて免疫組織化学染色(SPC+CC10+)を行って肺幹細胞微小環境の活性化状態(Leeら.(2014)上記)を判定する。
回復した青年期(4週齢)及び若年成熟(10週齢)のマウスにて肺機能の試験及び心エコー検査を行う。
マウスを3%のイソフルランで麻酔し、1~2%で継続させて350~450bpmの心拍を達成する。Vevo 2100超音波(Monash Bioimaging)及び40MHzの線形変換器を用いて、前方に角度をつけた左胸骨傍の長軸断面に沿った肺動脈加速時間のPWドップラー測定を行う。右胸骨傍の長軸断面に沿ったMモードを適用することによって右心室壁の厚さを測定する。侵襲性の肺機能検査について同じ群のマウスを使用する。それらは、インライン超音波ネブライザー、人工呼吸器、及び連結された圧変換器(FlexiVent,SCIREQ,Montreal,Canada)に接続する18Gのカニューレで気管切開される。気道抵抗及びコンプライアンスは漸増濃度のメタコリン(1~30mg/mL、サイクル当たり3分間)にマウスを曝露することによって評価する。強制呼気容量、肺活量及び深呼気量を得る。制約のない全身の容積脈波記録法とは異なって、これは動物の訓練を必要とせず、人工呼吸における短い中断を可能にして、その間に事前に定義された圧力又は容積の波形を測定する測定操作を実行する。これは、たとえば、過剰なデッドスペース及び測定不正確さのような容積脈波記録法にて直面する従来の難題を克服する。
hAECドナーの在胎期間はその回復能に対して重大な影響を有することができる(Limら.(2013),Placenta,34:486-492)。妊娠満期と妊娠満期前のhAECから回収されたエキソソームへの積み荷の間での比較を行う。準備では、妊娠満期及び妊娠満期前のドナーに由来する羊膜エキソソームが投与され、肺胞単純化は妊娠満期ドナーに由来する羊膜エキソソームを受け取った動物でのみ元に戻されることが示されるので、免疫調節及び再生の経路を活性化する能力は妊娠満期前の羊膜エキソソームでは有意に損なわれていることを示している。当初の存在/非存在のプロテオーム解析をエキソソームへの積み荷で実施すると、妊娠満期及び妊娠満期前のドナーについてそれぞれ242及び21の独特のタンパク質が特定されている。遺伝子オントロジーの解析を用いて、妊娠満期羊膜エキソソームが、創傷治癒、アポトーシス、血管発生、急性炎症、及び上皮細胞の発生に関連する細胞のシグナル伝達のメディエータを含有したことが見極められる。
羊膜エキソソームの再生促進性効果を気管支肺異形成症の新生児マウスモデルで実証した。妊娠満期又は妊娠満期前の羊膜組織に由来するエキソソームの投与に続いて肺胞プルーニングが観察された(図12A~D)。用語「BPD」は気管支肺異形成症のマウスモデル動物を意味する。
肺の再生を誘導する能力について、妊娠満期由来のヒトエキソソームをヒト羊膜上皮細胞(hAEC)と並べて調べた。結果を図13A~Cにて示す。妊娠満期エキソソームは、図13にて暗く染まった(エラスチン陽性)先端部で見られるように二次中隔稜(septal crests)を回復した。
四塩化炭素の週3回の腹腔内注射を12週間行うことによって8~12週齢の成熟マウスにて肝線維症を誘導した。8週目にエキソソーム(1μg)を週2回注射した。結果を図15A及びBにて示す。シリウスレッドアッセイ及びα平滑筋アクチン(SMA)発現アッセイを用いて生物線維性細胞を判定した。αSMAは線維芽細胞の収縮性で役割を担う。αSMAの発現は標準のアッセイを用いて判定し、シリウスレッド及びαSMAの陽性の面積を視野当たりで測定した。炎症性マクロファージタンパク質CCL4を使用した。CCL4+エキソソームは、CCL4+生理食塩水の対照に比べて視野当たりで有意に少ない線維性の細胞を生じた(図15A及びB)。
図16は、妊娠満期エキソソームと妊娠満期前hAECとの間でのプロテオームの積み荷がほぼ同じであることを示す。妊娠満期前hAECに対比させた妊娠満期hAECのプロテオームの積み荷の間ではさらに大きな差異があった。調べたタンパク質を表2a及び2bにてリストにする。hAECと総MSCの間での有用な細胞成分の比較を図17に示す。図18はhAECと総MSCの間での生物学的過程も比較する。
多発性硬化症の動物モデルにて羊膜エキソソームを調べる。エキソソームは再髄鞘形成を促進し、多発性硬化症と同様に、たとえば、視神経炎、デビック病、横断性脊髄炎、急性播種性脳脊髄炎、及び副腎白質ジストロフィ及び副腎脊髄ニューロパシーのような他の状態の治療に有用であることが期待される。
ヒト羊膜上皮細胞の馴化培地から単離されたエキソソームは免疫調節効果及び再生促進効果を有する。羊膜エキソソームは(他の因子の中でも)高いレベルのHLA-Gを含有する。
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Claims (3)
- 気管支肺異形成症を治療するための医薬組成物であって、
前記医薬組成物が、哺乳動物羊膜エキソソーム、および1以上の薬学上許容できる担体、賦形剤及び/又は希釈剤を含む、医薬組成物。 - 気管支肺異形成症を治療するための薬物の製造における哺乳動物羊膜エキソソームの使用。
- 気管支肺異形成症を治療するための改善された細胞に基づく治療用プロトコールのための医薬組成物であって、
前記医薬組成物が、不死化された羊膜上皮細胞株から単離された羊膜エキソソームを含む、医薬組成物。
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