JP5243040B2 - 創傷治癒および組織再生を促進するための組成物および方法 - Google Patents
創傷治癒および組織再生を促進するための組成物および方法 Download PDFInfo
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Description
本発明は、2004年12月21日に出願された米国仮特許出願第60/638,366号、および2005年4月15日に出願された米国仮特許出願第60/671,796号に優先権の利益を主張し、それらは参照によりその全体が本明細書中に包含される。
本発明は、国立衛生研究所により許可された補助金RO−I HL56728の下に、政府支援を受けてなされた。政府は、本発明に一定の権利を有する。
トカゲが尻尾を切り離すとき、それが最終的に増殖するだろうことは、平均的な子供に知られている。さらに、多くの下等動物が、損傷後の全四肢および臓器を含む、非常に複雑な構造を再生し得ることは、そのような事柄を勉強している子供達および大人によく理解される。例えば、魚類は、古い心臓のかなりの部分が削り取られた後、心臓を再び増殖することができる(Poss et al., 2002)。このことは、心臓が、ほとんどの動物の瞬間瞬間の生存に如何に不可欠であるかを考えるとき、驚くべき結果である。
アルファコネキシンのカルボキシ末端アミノ酸配列を含む単離されたポリペプチド(本明細書中、アルファコネキシン カルボキシ末端(ACT)ポリペプチドとも称される)、またはその保存的変異体を提供する。本明細書中、対象における組織損傷後の創傷治癒を促進する方法であって、1個以上の本発明に記載の組成物(例えば、ポリペプチド、核酸、またはベクター)および薬学的に許容される担体を該対象に投与することを含む方法を提供する。
本明細書中に包含され、本明細書の一部を構成する添付の図面は、開示した方法および組成物のいくつかの態様、ならびに開示した方法および組成物の原則を説明するのに用いる説明を記載する。
開示した方法および組成物は、下記の特定の態様の詳細な説明および本明細書中に包含される実施例、ならびに図面およびその上記および下記の説明を参照することにより、より容易に理解することができる。
故に、配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11または配列番号12のアミノ酸配列を含むポリペプチドをコードする単離された核酸を提供する。
対象における組織損傷後の創傷治癒を促進する方法であって、1個以上の本明細書で供される組成物(例えば、ポリペプチド、核酸、またはベクター)および薬学的に許容される担体を、該対象に投与することを含む方法を本明細書にて提供する。組織損傷を有する対象を処置する方法であって、1個以上の本明細書で供される組成物(例えば、ポリペプチド、核酸、またはベクター)および薬学的に許容される担体を、該対象に投与することを含む方法をさらに提供する。
本明細書で開示の組成物および開示の方法に必要な組成物を、特に他に記載がなければ、特定の試薬または化合物に関して当業者に公知の何らかの方法を用いて作製することができる。
上記の物質ならびに他の物質は、開示の方法を実行するのに有用なキット、または開示の方法の実行を補助するためのキットとして、何らかの適する組み合わせで共にパッケージされ得る。それは、特定のキット中のキット構成要素が、開示の方法において共に使用するために設計され適合されるとき有用である。例えば、創傷治癒を促進するためのキットであって、本明細書に記載の1個以上のポリペプチド、核酸またはベクターおよび薬学的に許容される担体を含むキットを開示する。かかるキットにはまた、ジェル、包帯、ミリポアテープ、薬用Qチップ、スプレー、ドロップ、シロップ、液体、使い捨てチューブまたはポーチが含まれ得る。キットはまた、生成物または製剤の適する使用および安全性の情報のための指示書を含み得る。キットは、医師により決定されるような、適用に基づく投与量情報および投与方法を含み得る。
開示の方法および組成物を、実験室研究ツールを含むが、これに限定されない多数の領域に適用可能である。これらの製剤は、例えば、細胞増殖、細胞移動のようないくつかの細胞過程において調節的役割を果たす。これらの製剤は、様々な細胞過程、細胞周期制御、細胞行動、細胞、臓器または組織の試験化合物などに対する応答を研究するための、インビトロおよびインビボモデル系の両方で実験室レベルで使用可能である。該製剤を、それらのみ、または他の化合物との組み合わせまたは細胞増殖分析のためのキットのようなキットの一部として提供することができる。該キットは、それらのみまたは他の化合物との組み合わせで本明細書に記載の製剤を含み得る。かかるキットは、実験を容易にするために設計された指示書を含み得る。他の使用が開示され、開示から明らかであり、および/または当業者に理解され得る。
新生仔ラット心臓由来の筋細胞を、標準プロトコールに従い組織培養ディッシュ上でコンフルエントに近い単層を形成するまで増殖させた。その後、その培養物を、30μM ACT 1 ペプチド(配列番号2)、30μM 非活性対照ペプチド(配列番号55)を含む培養培地、またはACTペプチドを含まないかまたは対照ペプチドを含むリン酸緩衝生理食塩水(PBS)中、さらに5日間培養した。非活性対照ペプチドは、カルボキシ末端を有するポリペプチドを含み、ここで、ACTペプチド配列は逆であった。ACTおよび対照ペプチドのアミノ末端を両方ともビオチン化し、標準的顕微鏡法またはビオチンとの結合に高親和性のストレプトアビジンに基づく生化学的方法を用いて、細胞質中のペプチドの検出(すなわち、分析)が可能である。
一腹の新生仔マウスを、低体温法を用いて脱感作した。4mm長の切開皮膚損傷を、肩甲骨間の背側正中線の皮膚(下層にある筋肉のレベルに至る)の全層に外科用メスを用いて作製した。その後、含まない(対照)または60μM濃度でACT 1 ペプチド(配列番号2)を溶解して含む20% pluronic(F−127)ゲル溶液30μlを、切開した損傷に用いた。Pluronicゲルは、ミセルでのACTペプチドの均一分散を補助し得る弱い界面活性特性を有する。より重要なことは、20%pluronicゲルは、15℃以下の温度で液体であるが、体温(37℃)で重合化する。このpluronicゲルの特性は、恐らく、ペプチドを創傷のプロテアーゼに富む環境下で分解から保護し、また、ペプチドの活性濃度がより長時間維持されるのを可能にする、切開損傷部位での組織中へのペプチドの制御放出を補助した。対照またはACTペプチドを含むゲルを、最初の適用後連続して24時間用いた。対照およびACTペプチド含有ゲルを、第二の適用後にはさらに適用しなかった。48時間後、ACTペプチド処理損傷(図5a)が、ACTペプチドを受容しない対照損傷(図5b)よりも外見上、かなり閉傷し、炎症が少なく、腫れが少なく(創傷端の突起に注目のこと)、ならびに一般的により治癒したことを特記できる。炎症におけるこれらの相違である対照処理損傷とACTペプチド処理損傷との間の腫れおよび治癒が、72(図5c、d)および96(図5e、f)時間点で持続した。7日目に、ACTペプチド創傷(図5g)は、対照ペプチド処理損傷(図5h)より平滑になり、瘢痕化の出現は少なかった。同じ動物における同じ損傷の画像が、治癒経時変化中の異なる時間点で示されることを特記する。
急性脊髄損傷を有する対象は、機能の小さな神経学的な回復さえ、それらのその後の独立に重要な影響を与え得る、重大な問題のある群を示す。一例において、急性脊髄損傷を有する対象に、急性脊髄損傷部位に直接、8時間以内に15分かけてACTペプチド(例えば、配列番号1)の0.02%から0.1%溶液をボーラス投与し、次いで45分後、その後23から48時間、ACTペプチドの0.01%溶液を注入した。別の例において、ACTペプチドを、急性脊髄損傷部位、または急性脊髄損傷領域を越える神経再接続を促進するように設計された培養生体骨格(tissue engineered bioscaffold)中に直接、8時間以内に負荷した遅延放出ナノ粒子をコートするために用いる。機能の改善を、運動活性、針を刺した皮膚の感受性および感覚の回復を測定するために設計された評価を含む神経学的転帰検査により、処置後一定間隔(例えば、6、12、26および52週)で医師により評価する。
ACTペプチド(n=12)および対照(N=8)の5mm直径の切除皮膚創傷を、上記の成体マウスに作製した。その後、創縫合率の定量的評価、再生した毛嚢の計数および引張強度測定を、最初の損傷後90日までの時間点で、創傷を受けた皮膚に行う。対照創傷と比較して、縫合(closure)は、ペプチド処理の24時間以内に顕著に増大した。同様に、10日目にて、ほとんどの創傷の縫合が完了間近なとき、極めて大きな相違が、ACTペプチド処理創傷が対照創傷よりも平均43%小さいように維持されていた。10日目に、ACTペプチド創傷は、対照創傷よりも、治癒創傷の単位面積当たり再生した毛嚢の数の有意な3.2倍増加を示した。
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Claims (60)
- 対象における組織損傷後の治癒を促進するための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
- 該医薬組成物が創縫合を促進する、請求項1に記載の医薬組成物。
- 該医薬組成物が瘢痕形成を低減する、請求項1に記載の医薬組成物。
- 該医薬組成物が組織再生を促進する、請求項1に記載の医薬組成物。
- 該医薬組成物が、該組織の破壊に必要な圧力(stress)または張力(strain)を増大する、請求項1に記載の医薬組成物。
- 該医薬組成物が、該組織における幹細胞分化を促進する、請求項1に記載の医薬組成物。
- 対象における組織の炎症を軽減するための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
- 対象における線維性組織形成を低減するための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
- 該対象が美容整形を受けている、請求項1から8のいずれか一項に記載の医薬組成物。
- 該組織損傷が、切屑(scrape)、切断、切開、火傷、褥創、身体の刺し傷、咬創、刺創、銃創、外科創傷、伸展損傷、挫滅、圧迫損傷、骨折、捻挫、損傷(strain)、発作、梗塞、動脈瘤、ヘルニア形成、虚血、瘻孔化、脱臼、放射線、細胞、組織または臓器移植、または癌の結果生じる、請求項1に記載の医薬組成物。
- 該組織損傷が、皮膚損傷、筋肉損傷、脳損傷、眼損傷、または脊髄損傷である、請求項1に記載の医薬組成物。
- 該組織損傷が、関節損傷、背部損傷、心臓損傷、血管系損傷、軟組織損傷、軟骨損傷、リンパ節損傷、腱損傷、靱帯損傷、または腹部損傷である、請求項1に記載の医薬組成物。
- 該ポリペプチドが、アルファコネキシンのカルボキシ末端の5から19個の隣接アミノ酸を含む、請求項1に記載の医薬組成物。
- 該変異体が、カルボキシ末端アミノ酸配列からの1個のアミノ酸の欠失を含む、請求項1に記載の医薬組成物。
- 該アルファコネキシンが、コネキシン30.2、コネキシン31.9、コネキシン33、コネキシン35、コネキシン36、コネキシン37、コネキシン38、コネキシン39、コネキシン39.9、コネキシン40、コネキシン40.1、コネキシン43、コネキシン43.4、コネキシン44、コネキシン44.2、コネキシン44.1、コネキシン45、コネキシン46、コネキシン46.6、コネキシン47、コネキシン49、コネキシン50、コネキシン56またはコネキシン59からなる群から選択される、請求項1に記載の医薬組成物。
- 該アルファコネキシンが、コネキシン37、コネキシン40、コネキシン43、またはコネキシン45である、請求項1に記載の医薬組成物。
- 該ポリペプチドが、配列番号1、配列番号2、配列番号3、配列番号4および配列番号5からなる群から選択されるアミノ酸配列を含む、請求項16に記載の医薬組成物。
- 該ポリペプチドが、配列番号2のアミノ酸配列を含む、請求項17に記載の医薬組成物。
- 該ポリペプチドが、配列番号1のC末端の9アミノ酸と少なくとも90%の同一性を有するアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 該ポリペプチドが、細胞内在化配列をさらに含む、請求項1に記載の医薬組成物。
- 該細胞内在化配列が、アンテナペディア、TAT、HIV−Tat、ペネトラチン、Antp−3A(Antp変異体)、ブフォリンII、トランスポルタン、MAP(モデル両親媒性ペプチド)、K−FGF、Ku70、プリオン、pVEC、Pep−1、SynBl、Pep−7、HN−I、BGSC(ビス−グアニジン−スペルミジン−コレステロール)、およびBGTC(ビス−グアニジン−トレン−コレステロール)からなる群から選択されるタンパク質のアミノ酸配列を含む、請求項20に記載の医薬組成物。
- 該細胞内在化配列がアンテナペディアであり、該配列が、配列番号7のアミノ酸配列を含む、請求項21に記載の医薬組成物。
- 該ポリペプチドが、配列番号8、配列番号9、配列番号10、配列番号11、および配列番号12からなる群から選択されるアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 損傷前に細胞または組織を予め処理するための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
- アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む組成物であって、局所投与のための製剤である、組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、組成物。
- 該組成物がコラーゲンビヒクル溶液である、請求項25に記載の組成物。
- 該製剤が、軟膏、ローション、クリームまたはジェルである、請求項25に記載の組成物。
- 該ジェルがpluronic(登録商標)ジェルである、請求項27に記載の組成物。
- 該製剤がポロキサマーを含む、請求項27に記載の組成物。
- 該ポリペプチドが、アルファコネキシンのカルボキシ末端の5から19個の隣接アミノ酸を含む、請求項25に記載の組成物。
- 該アルファコネキシンが、コネキシン30.2、コネキシン31.9、コネキシン33、コネキシン35、コネキシン36、コネキシン37、コネキシン38、コネキシン39、コネキシン39.9、コネキシン40、コネキシン40.1、コネキシン43、コネキシン43.4、コネキシン44、コネキシン44.2、コネキシン44.1、コネキシン45、コネキシン46、コネキシン46.6、コネキシン47、コネキシン49、コネキシン50、コネキシン56またはコネキシン59からなる群から選択される、請求項25に記載の組成物。
- 該アルファコネキシンが、コネキシン37、コネキシン40、コネキシン43、またはコネキシン45である、請求項25に記載の組成物。
- 該ポリペプチドが、配列番号1、配列番号2、配列番号3、配列番号4および配列番号5からなる群から選択されるアミノ酸配列を含む、請求項32に記載の組成物。
- 該ポリペプチドが、配列番号2のアミノ酸配列を含む、請求項33に記載の組成物。
- 該ポリペプチドが、配列番号2と少なくとも90%の同一性を有するアミノ酸配列を含む、請求項25に記載の組成物。
- 該ポリペプチドが、細胞内在化配列をさらに含む、請求項25に記載の組成物。
- 該細胞内在化配列が、アンテナペディア、TAT、HIV−Tat、ペネトラチン、Antp−3A(Antp変異体)、ブフォリンII、トランスポルタン、MAP(モデル両親媒性ペプチド)、K−FGF、Ku70、プリオン、pVEC、Pep−1、SynBl、Pep−7、HN−I、BGSC(ビス−グアニジン−スペルミジン−コレステロール)、およびBGTC(ビス−グアニジン−トレン−コレステロール)からなる群から選択されるタンパク質のアミノ酸配列を含む、請求項36に記載の組成物。
- 該細胞内在化配列がアンテナペディアであり、該配列が、配列番号7のアミノ酸配列を含む、請求項37に記載の組成物。
- 該ポリペプチドが、配列番号8、配列番号9、配列番号10、配列番号11および配列番号12からなる群から選択されるアミノ酸配列を含む、請求項25に記載の組成物。
- 抗生物質、ステロイド、鎮痛剤、抗炎症剤、抗ヒスタミン剤、化学療法剤、または他の治療ペプチド、またはそれらの組み合わせをさらに含む、請求項25に記載の組成物。
- 対象における組織損傷後の治癒を促進するためのキットであって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含むポリペプチド;および、薬学的に許容される担体を含み、ジェル、包帯、スプレー、ドロップ、シロップ、液体、使い捨てチューブまたはポーチをさらに含む、キットであって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、キット。
- アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドの、組織治癒を促進するための薬剤の製造における使用であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、使用。
- 組織治癒を促進するための薬剤の製造における配列番号2のアミノ酸配列の使用。
- コネキシン37のカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドであって、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させ、さらに細胞内在化配列を含む、ポリペプチド。
- 該ポリペプチドが、コネキシン37のカルボキシ末端の5から19個の隣接アミノ酸を含む、請求項44に記載の単離されたポリペプチド。
- 該ポリペプチドが、配列番号43と少なくとも90%の同一性を有するアミノ酸配列を含む、請求項44に記載の単離されたポリペプチド。
- 配列番号3、4、5、10、11および12からなる群から選択されるアミノ酸配列を含む、単離されたポリペプチド。
- 対象における組織損傷後の治癒を促進するための物質であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含むポリペプチドでコートされた物質であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、物質。
- 該物質が人工物質(bio-engineered material)である、請求項48に記載の物質。
- 該物質が培養骨格(tissue engineered scaffold)である、請求項48に記載の物質。
- 該物質が、義四肢、乳房インプラント、陰茎インプラント、精巣インプラント、義眼、顔面インプラント、人工関節、人工心臓弁、人工血管、義歯、顔面補綴、傾斜円板弁(tilted disc valve)、ケージドボール弁(caged ball valve)、義耳、義鼻、人工内耳、および皮膚代替物からなる群から選択される医用移植片である、請求項48に記載の物質。
- 該物質が、包帯、絆創膏(steri−strip)、縫合糸、ステープル、または移植片からなる群から選択される、請求項48に記載の物質。
- 創傷部位における線維芽細胞移動を阻止するための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
- 炎症反応を生じる事象後の炎症細胞移動を低減するための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
- 該炎症細胞が好中球である、請求項54に記載の医薬組成物。
- 炎症反応を生じる事象後の炎症細胞の密度を低下するための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
- 創傷部位の再上皮形成のための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
- 損傷後の毛嚢の再生のための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
- 星状細胞の密度を低下するための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
- 脳損傷後のニューロンの密度を増加するための医薬組成物であって、アルファコネキシンのカルボキシ末端アミノ酸配列の4から30個の隣接アミノ酸、または前記隣接アミノ酸と少なくとも90%の同一性を有するその変異体を含む単離されたポリペプチドを含む、医薬組成物であって、前記ポリペプチドは、全長アルファコネキシンタンパク質を含まず、コネキシンにより形成されるギャップ結合チャネル重合の範囲を増加させる、医薬組成物。
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