JP6545102B2 - 心病態を治療する方法 - Google Patents
心病態を治療する方法 Download PDFInfo
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Description
本発明は部分的には、十分な量の改変胎盤組織または胎盤組織抽出物の使用によって心病態を治療する方法に関する。
心血管疾患は、患者の管理および治療に進歩がみられるものの、依然として世界で最も大きな死因となっている。
本開示を開示し説明する前に、以下に記載する態様は特定の組成物、合成方法または使用に限定されるわけではなく、したがって、当然のことながら多様なものになり得ることを理解するべきである。このほか、本明細書で使用される用語は単に特定の態様を説明するのが目的であって、限定することを意図するものではないことを理解するべきである。
心筋などの心臓組織が、例えば心臓発作で損傷した場合、幹細胞を動員して修復することができる。しかし、心臓には修復が完了する前に幹細胞へのシグナル伝達を停止する傾向があると考えられている。その結果、損傷組織の修復が部分的なものにとどまり、これが心臓への負担となって心臓をさらに激しく非効率的に働かせることになり、ひいては心臓になおも有害な作用をもたらす可能性がある。さらに、現在用いられている損傷組織に幹細胞を注射する治療法は、注射した幹細胞の生存率が低いことにより複雑なものとなっている。
この実施例で微粒化粒子の作製に使用する羊膜/絨毛膜組織グラフトを、米国特許出願公開第2008/0046095号(その全体が参照により組み込まれる)に記載されている工程により作製した。50mLバイアルに組織グラフト(4cm×3cm)と9.5mmの粉砕鋼球2個を入れた後、バイアルを密閉した。バイアルを凍結ブロックに入れ、凍結ブロックを凍結棚に入れた。凍結棚を液体窒素の入ったジュワー瓶に入れた。組織試料を30〜60分以内で気相冷却した。ジュワー瓶から凍結棚を取り出し、凍結棚から凍結ブロックを取り出した。凍結ブロックを粉砕機(SPEX Sample Prep GenoGrinder 2010)の中に入れ、1,500rpm、20分に設定した。20分経過した後、組織を検査して微粒化を確認した。必要であれば、組織をさらに30〜60分間、再びジュワー瓶に入れ、粉砕機に移してさらに20分間、十分に微粒化した。組織が十分に微粒化された後、一連の米国標準ASTMふるいを用いて分級した。ふるいは次のような順序で設置した:355μm、300μm、250μm、150μmおよび125μm。微粒化した材料を50mLバイアルから355μmのふるいに移した。微粒化粒子を十分に分離するため、各ふるいを個別に振動させた。ふるいを用いて微粒化粒子を効率的に分離した後、粒子径が355μm、300μm、250μm、150μmおよび125μmの微粒化粒子を別々のバイアルに収集した。
本明細書に記載される改変胎盤組織、組成物および方法に様々な修正を施すことができる。本明細書を検討し、本明細書に開示される改変胎盤組織、組成物および方法を実践すれば、本明細書に記載される改変胎盤組織、組成物および方法のその他の態様が明らかになるであろう。本明細書および実施例は例示的なものとして見なされることが意図される。
ヒト間葉系幹細胞(ヒトMSC)をEpiFix(登録商標)試料の存在下で細胞培養して評価し、EpiFix(登録商標)がヒトMSCの遊走を誘導するかどうかを明らかにした。EpiFix(登録商標)はインタクトの上皮層を有する羊膜と絨毛膜の層である。
底部に8μm孔膜フィルターを備えた24ウェル細胞培養インサートで標準的な遊走アッセイを実施した(図1を参照されたい;BD Biosciences)。実験開始24時間前、ヒトMSC(ドナー1例、3代目)を無血清培地で培養し、フィブロネクチンをPBSに溶かした5μg/mLの溶液300μLを各細胞培養インサートに入れて、一晩、フィブロネクチンを細胞培養インサートの表面に吸着させた。
最小量のEpiFix(登録商標)試料を含有する「低」群(直径1.5mmの円盤状)と無血清陰性対照との間に有意差はみられなかった(図2の棒グラフを参照されたい)。「中」群(直径4mmの円盤状)および「高」群(12×13mmの四角形を3〜4mmの四角形に切り分けたもの)はともに無血清対照よりも統計学的に有意に高く(対照に比して約60%および75%の遊走;図2を参照されたい)、EpiFix(登録商標)が細胞遊走を刺激することを示していた。「高」群と「中」群との間に統計学的有意差はみられなかった。以上の結果は、EpiFix(登録商標)製品がヒト間葉系幹細胞を誘引する1つまたは複数の因子を含有することを示している。
正常マウスに移植したEpiFix(登録商標)が幹細胞/前駆細胞の動員を引き起こすかどうかを明らかにするため、マウス造血幹細胞(HSC)およびマウス間葉系幹細胞(マウスMSC)に焦点を絞って試験を実施した。
正常マウスにおける移植にドナー6例のEpiFix(登録商標)製品を用いた。5mm四方のEpiFix(登録商標)を4か月齢のFVB/NJマウス(体重約23.50g〜約30g)の皮下に外科的に移植した。1つの試料につき1時点当たり4匹のマウスに移植を実施した。時点は3日後、7日後、14日後および28日後とした。陰性対照は皮膚が正常で偽手術を実施する(外科的切開は実施するが、移植は実施しない)マウスとした。細胞を除去した皮膚マトリックス(無細胞皮膚マトリックス;ADM)を比較移植物(I型コラーゲンを含むが、サイトカインは含まない)として用いた。蛍光標示式細胞分取(FACS)に移植物およびそれを覆う皮膚を回収した。
EpiFix(登録商標)移植後第7日、第14日および第28日、陰性対照に比してマウスHSCの有意な増加がみられた(図3Aを参照されたい)。第28日、EpiFix(登録商標)試料に依然としてADMに比してマウスHSCの有意な増加がみられた。
マウスのEpiFix(登録商標)移植部位に動員される幹細胞を特徴付けるため、フローサイトメトリーおよび免疫組織化学を用いて試験を実施した。
4か月齢のFVB/NJマウス16匹の背中に皮膚切開を実施して、Purion(登録商標)処理した無菌EpiFix(登録商標)(MiMedx社から入手)の5mm四方のパッチを皮下に移植した。また別のマウス16匹に同じ皮膚切開を実施して対照治療(偽手術)とした。コラーゲン足場と比較するため、細胞を除去したヒト真皮(無細胞皮膚マトリックス;ADM)の5mm四方のパッチをマウス16匹の皮下に移植した。分析には未手術マウスを「正常な」背中の皮膚の入手源として用いた。
陰性対照との比較では、第14日および第28日にEpiFix(登録商標)移植物周囲の組織に造血前駆細胞(HPC)レベルの有意な上昇がみられた。コラーゲン足場ADM対照との比較では、第14日および第28日にEpiFix(登録商標)移植物周囲の組織に造血前駆細胞の有意な増加がみられた。
AmnioFix(登録商標)膜およびEpiFix(登録商標)膜が急性心筋梗塞(MI)後の梗塞の大きさおよび心リモデリングを含めた心臓修復に及ぼす効果を検討するため試験を実施した。AmnioFix(登録商標)およびEpiFix(登録商標)(MiMedx社から入手)はともに羊膜に由来し、構造的コラーゲンおよび細胞外マトリックスタンパク質のほか、PDGF−AA、PDGF−BB、TGFα、TGFβ、bFGF、EGF、VEGF、IL−10、IL−4、PlGF、TIMP−1,TIMP−2およびTIMP−4を含めた多数の成長因子およびサイトカインを含有する。
この実験は、異種移植片のAmnioFix(登録商標)膜またはEpiFix(登録商標)膜に応答して免疫系が関与するあらゆる可能性を排除するべく、免疫不全NOD/SCIDマウスを用いて実施したものである。野生型マウスを比較に用いた。
AmnioFix(登録商標)膜で処置したマウスおよびEpiFix(登録商標)膜で処置したマウスではともに、対照(生理食塩水)処置マウスに比して冠動脈結紮後の梗塞領域が減少していた(図4Aおよび4B)。EpiFix(登録商標)処置マウスとAmnioFix(登録商標)処置マウスの間に梗塞の大きさの統計学的有意差はみられなかった。数匹のマウスが冠動脈結紮から回復しなかったが、これは術後の膜による処置ではなく外科手術による死亡が原因であった。
Claims (14)
- 損傷した心臓組織付近の領域にその機能を妨害することなく適用するよう構成された脱水された改変胎盤組織または脱水された改変胎盤組織抽出物を、損傷を軽減し治癒を誘導するのに十分な量で含む、損傷または罹患した心臓組織を治療するための組成物であって、
前記改変胎盤組織が線維芽細胞層を有する羊膜を含み、ここで前記羊膜は、絨毛膜上に直接積層されており、
前記改変胎盤組織が、造血幹細胞または間葉系幹細胞を動員する有効量の幹細胞動員因子を保持している、組成物。 - 前記改変胎盤組織が、有効量の成長因子および/または血管新生誘導因子を保持している、請求項1に記載の組成物。
- 前記改変胎盤組織が、PDGF−AA、PDGF−BB、TGFa、TGFβ、bFGF、EGF、VEGF、IL−10、IL−4、PlGF、TIMP−1、TIMP−2およびTIMP−4のうちの1つまたは複数を含む、請求項1に記載の組成物。
- パッチである、請求項1〜3のいずれか1項に記載の組成物。
- 前記改変胎盤組織が微粒化されている、請求項1〜3のいずれか1項に記載の組成物。
- 注射可能な形態である、請求項1〜3のいずれか1項に記載の組成物。
- 前記損傷または罹患した心臓組織が、虚血、急性心筋梗塞、心筋梗塞、心筋症、不安定狭心症、難治性狭心症、心臓発作、心不全、肺性心、静脈移植片疾患、冠動脈心疾患、閉塞性冠動脈血栓、心臓弁膜症、炎症性心肥大、アテローム性動脈硬化症、急性心外膜炎およびドレスラー症候群、炎症性心病態または壊死性心病態を原因とするものである、請求項1に記載の組成物。
- 前記脱水された改変胎盤組織または脱水された前記改変胎盤組織抽出物が、前記領域と接触して貼付されたときに前記領域への幹細胞動員を促進する、請求項1に記載の組成物。
- 前記組成物が有効量の成長因子を含む、請求項2に記載の組成物。
- 前記組成物が有効量の血管新生誘導因子を含む、請求項2に記載の組成物。
- 前記組成物によって多能性幹細胞が動員される、請求項3に記載の組成物。
- 胎盤組織が、治療する領域に幹細胞を動員するのに十分な質量を有する、請求項1〜11のいずれか1項に記載の組成物。
- 前記損傷または罹患した心臓組織が、炎症性心病態または壊死性心病態を原因とするものである、請求項1に記載の組成物。
- 血管新生を誘導するために用いられる、請求項13に記載の組成物。
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