JP2005523708A - プラスミノーゲンアクチベーター阻害剤−1を阻害するためのdna酵素 - Google Patents
プラスミノーゲンアクチベーター阻害剤−1を阻害するためのdna酵素 Download PDFInfo
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Abstract
発明もmRNAをPAI-1をコードして、特異的に翻訳を阻害するアンチセンス・オリゴヌクレオチドを提供する本。
本発明も、PAI-1の発現を阻害する種々の方法を提供する、
および
疾患を治療する方法このような。
最後に、本発明は直前に記載のDNAzymesを含む薬学的組成物を提供する、
リボザイム、
アンチセンス・オリゴヌクレオチド、
または、活性成分としてのPAI-1発現のその他の阻害剤。
Description
心筋梗塞後において、その後の心筋細胞ネクローシスが、冒された心筋内への炎症性細胞の遊走、細胞外基質の分解、および新血管新生によって特徴づけられる創傷治癒反応を刺激する。これらの成分のそれぞれは、プラスミン(これは、浸潤している骨髄由来細胞の表面上に発現されるウロキナーゼ型プラスミノーゲンアクチベータ(u-PA)による活性化を介してプラスミノーゲンに由来する)による潜在性のメタロプロテイナーゼの活性化を必要とすると考えられる(1-3)。さらに最近には、細胞表面u-PAの役割は、細胞遊走に必要な隠れた細胞接着部位の暴露を容易にすることである可能性が示唆された(4)。これは、u-PAとプラスミノーゲンアクチベーター阻害剤-1(PAI-1)(これは、その天然の状態において、ビトロネクチンと複合対を形成する)の間の直接的な相互作用に関与すると思われる(4、5)。u-PAなどのプロテイナーゼとPAI-1の反応は、迅速に高次構造の変化を生じ、これをビトロネクチンから分離させ、低密度リポタンパク質受容体に対するその親和性を増大させ(6)、そのクリアランスおよび分解を引き起こす。ビトロネクチンからのPAI-1の除去により、そのリガンドのもう一つであるインテグリンαvβ3に対する結合のために必要なビトロネクチン上のエピトープが曝露する(4、7)。細胞表面インテグリンαvβ3と組織ビトロネクチンの間の相互作用は、血管形成の発生に重要なことが示されたので(4、8、9)、本発明者らは、心筋梗塞後の過剰のPAI-1タンパク質の発現が、骨髄に由来する血管芽細胞による最適な新血管新生を防げるのかもしれず、またPAI-1発現の阻害が、新血管新生を促進するであろうと仮定した。
本発明は、プラスミノーゲンアクチベーター阻害剤-1(PAI-1)をコードするmRNAを特異的に切断する触媒核酸であって、5’から3’の向きに:
(a)少なくとも4ヌクレオチドの第1の結合ドメインを定義する連続したヌクレオチド;
(b)前記第1の結合ドメインの3’末端に近接して位置する触媒ドメインを定義し、かつPAI-1コードするmRNAを所定のホスホジエステル結合で切断することができる連続したヌクレオチド;および、
(c)前記触媒ドメインの3’末端に近接して位置する少なくとも4ヌクレオチドの第2の結合ドメインを定義する連続したヌクレオチドを含み、
前記それぞれの結合ドメインのヌクレオチドの配列は、前記PAI-1をコードするmRNAの一連のリボヌクレオチドに相補的であり、および前記触媒核酸は、PAI-1をコードするmRNAにハイブリダイズし、かつ特異的に切断する触媒核酸を提供する。
本明細書において使用されるものとして、他に言及しない限り、以下のそれぞれの用語は、以下に記載の定義を有するものとする。
(a)少なくとも4ヌクレオチドの第1の結合ドメインを定義する連続したヌクレオチド;
(b)前記第1の結合ドメインの3’末端に近接して位置する触媒ドメインを定義し、かつPAI-1コードするmRNAを所定のホスホジエステル結合で切断することができる連続したヌクレオチド;および、
(c)前記触媒ドメインの3’末端に近接して位置する少なくとも4ヌクレオチドの第2の結合ドメインを定義する連続したヌクレオチドを含み、
前記それぞれの結合ドメインのヌクレオチドの配列は、前記PAI-1をコードするmRNAの一連のリボヌクレオチドに相補的であり、および前記触媒核酸は、PAI-1をコードするmRNAにハイブリダイズし、かつ特異的に切断する触媒核酸を提供する。
製剤は、従来の混合、顆粒化、糖衣丸を作製、溶解、または凍結乾燥プロセスによって作製されてもよい。使用されるプロセスは、使用される活性成分の最終的に物性に依存する。
1つの態様において、直前に記載のオリゴヌクレオペプチド(oligonucleoptide)のヌクレオチドは、少なくとも1つのデオキシリボヌクレオチドで含む。もう一つの態様において、ヌクレオチドは、少なくとも1つのリボヌクレオチドで含む。このようなデオキシリボヌクレオチドまたはリボヌクレオチドは、前述のように修飾または誘導体化することができる。
ヒトおよびラットPAI-1 mRNAをターゲットするDNA酵素の構築。
気管支肺胞洗浄(BAL)の上静液中のPAI-1レベルは、健常人におけるよりも特発性肺線維症(IPF)の患者において有意に高い。特発性肺線維症の肺では、凝血原および抗フィブリン溶解性の活性が増大された。したがって、PAI-1は、肺線維症への治療的な介入のための適切な標的であると思われる。
PAI-1レベルは、心筋梗塞患者において、特に糖尿病患者において、末梢の動脈疾患において、特に糖尿病患者において、およびバルーン血管形成術および/またはステント移植および再狭窄に非常に上昇する。PAI-1レベルの上昇により、活性化されたプロテインCのレベルが減少し、これにより、トロンビン生成、フィブリン、および血餅形成の増大を生じる。トロンビンは、バルーン血管形成術またはステント移植後の再狭窄の特徴である平滑筋細胞の遊走および増殖を誘導する。
DNA酵素およびRNA基質:3'-3'の反転チミジンを有するDNA酵素は、組み込みDNA技術(Integrated DNA technologies)(Coralville(IA))によって合成し、RNA分解酵素フリーのIE-HPLCまたはRP-HPLCによって精製した。標的DNA酵素に対応する短いRNA基質を化学的に合成し、続いてRNAseフリーのPAGEで精製し、またDNA鋳型からのインビトロ転写によっても作製した。
, Missouri)。次いで、アビジン-ビオチン複合体(Vector Laboratories, Burlingame, CA)をさらに30分間添加して、筋細胞をDAB溶液混合物(Sigma, Saint Louis, Missouri)に5分照射に続いて褐色に視覚化した。組織切片を40×の拡大率で顕微鏡によって検査し、少なくとも100個の細胞を少なくとも8個の強拡大の視野において計数した。アポトーシスの筋細胞の割合は、アポトーシスインデックスで測定し;アポトーシスのインデックスは、ポジティブ染色の筋細胞核の数を筋細胞核の総数によって割り、100をかけることによって算出した。組織の縁において染色された細胞は、計数しなかった。1以下のアポトーシスインデックスは、アポトーシスの非存在を示すとみなした。
SD系のハーラン、Indianapolis、IN)をケタミン(90mg/kgのi.p.)およびキシラジン(10mg/kgのi.p.)によって麻酔し、2F塞栓摘出バルーンカテーテル(Baxter Health Care)を外側の動脈を経由して左総頚動脈に導入した。バルーンを空気によって膨張させて、総頚動脈を膨張させ、次いで外側の動脈に取り除いた。この手順を3回繰り返し、次いでカテーテルを除去した。左総頚動脈のバルーン傷害の後、傷害から遠い部分を一時的な結紮法によって分離した。PAI-1またはスクランブルされた対照DNAzymeを遠くの傷害部分に注入し、室温で5分間インキュベートした。インキュベーション後、カニューレを除去して、総頚動脈に対する血流を回復した。バルーン傷害の2週後、ラットを麻酔さして左右の頸動脈を除去してパラフィンに包埋した。それぞれの動脈を3つの部分に分割して、別々にパラフィンに包埋した。横断面のリング(5μm)をそれぞれの部分から切除し、ヘマトキシリン‐エオジンで染色した。スライドを40×の拡大率で顕微鏡によって撮した。内腔、新内膜、および媒体類領域をNIH Image 1.60ソフトウェア・パッケージを用いて測定した。領域の測定は、内腔周辺(内腔領域[LA]、Um2)、新内膜周辺(内膜領域[IA]、Um2)、および外部弾性薄膜(external elastic lamina)(血管領域[VA]、Um2)トレースすることによって得た。破損の長さに対する内膜領域の比(IA/FL)を得て、傷害の範囲に対して補正した。測定は、治療について盲検とした観察者によって行った。
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Claims (79)
- プラスミノーゲンアクチベーター阻害剤-1(PAI-1)をコードするmRNAを特異的に切断する触媒核酸であって、5’から3’の向きに:
(a)少なくとも4ヌクレオチドの第1の結合ドメインを定義する連続したヌクレオチド;
(b)前記第1の結合ドメインの3’末端に近接して位置する触媒ドメインを定義し、かつPAI-1コードするmRNAを所定のホスホジエステル結合で切断することができる連続したヌクレオチド;および、
(c)前記触媒ドメインの3’末端に近接して位置する少なくとも4ヌクレオチドの第2の結合ドメインを定義する連続したヌクレオチドを含み、
前記それぞれの結合ドメインのヌクレオチドの配列は、前記PAI-1をコードするmRNAの一連のリボヌクレオチドに相補的であり、および前記触媒核酸は、PAI-1をコードするmRNAにハイブリダイズし、かつ特異的に切断する触媒核酸。 - 前記第1の結合ドメインのヌクレオチドが、少なくとも1つのデオキシリボヌクレオチドを含む、請求項1の触媒核酸。
- 前記第2の結合ドメインのヌクレオチドが、少なくとも1つのデオキシリボヌクレオチドを含む、請求項1の触媒核酸。
- 前記第1の結合ドメインのヌクレオチドが、少なくとも1つのデオキシリボヌクレオチド誘導体を含む、請求項1の触媒核酸。
- 前記第2の結合ドメインのヌクレオチドが、少なくとも1つのデオキシリボヌクレオチド誘導体を含む、請求項1の触媒核酸。
- 前記第1の結合ドメインのヌクレオチドが、少なくとも1つのリボヌクレオチドを含む、請求項1の触媒核酸。
- 前記第2の結合ドメインのヌクレオチドが、少なくとも1つのリボヌクレオチドを含む、請求項1の触媒核酸。
- 前記第1の結合ドメインのヌクレオチドが、少なくとも1つのリボヌクレオチド誘導体を含む、請求項1の触媒核酸。
- 前記第2の結合ドメインのヌクレオチドが、少なくとも1つのリボヌクレオチド誘導体を含む、請求項1の触媒核酸。
- 前記第1の結合ドメインのヌクレオチドが、少なくとも1つの修飾塩基を含む、請求項1の触媒核酸。
- 前記第2の結合ドメインのヌクレオチドが、少なくとも1つの修飾塩基を含む、請求項1の触媒核酸。
- 前記第1の結合ドメインのヌクレオチドが、少なくとも1つの修飾されたヌクレオシド間結合を含む、請求項1の触媒核酸。
- 前記第2の結合ドメインのヌクレオチドが、少なくとも1つの修飾されたヌクレオシド間結合を含む、請求項1の触媒核酸。
- 前記修飾されたヌクレオシド間結合が、ホスホロチオネート結合である、請求項12または13の触媒核酸。
- PAI-1をコードするmRNAが、ヒトPAI-1をコードする、請求項1の触媒核酸。
- 前記ヒトPAI-1をコードするmRNAが、配列番号:5に記載された配列を有する、請求項15の触媒核酸。
- 請求項1に記載の触媒核酸および薬学的に許容されるキャリアを含む薬学的組成物。
- 発現を阻害しなければPAI-1を発現する細胞におけるPAI-1の発現を特異的に阻害する方法であって、前記細胞におけるPAI-1の発現を特異的に阻害するために、請求項1に記載の触媒核酸と前記細胞を接触させることを含む方法。
- 被検体の細胞におけるPAI-1の発現を特異的に阻害する方法であって、被検体の細胞におけるPAI-1の発現を特異的に阻害するために有効な請求項1に記載の触媒核酸の量を被検体に投与することを含む方法。
- 被検体の細胞におけるPAI-1の発現を特異的に阻害する方法であって、前記被検体の細胞におけるPAI-1の発現を特異的に阻害するために有効な請求項17に記載の薬学的組成物の量を前記被検体に投与することを含む方法。
- 被検体の心筋細胞のアポトーシスを含む被検体の循環器病を治療する方法であって、前記被検体の心筋細胞のアポトーシスを阻害するために有効な請求項17の薬学的組成物の量を前記被検体に投与して、これにより循環器病を治療することを含む方法。
- 被検体の新内膜形成を含む被検体の循環器病を治療する方法であって、前記被検体の新内膜形成を阻害するために有効な請求項17に記載の薬学的組成物の量を前記被検体に投与して、これにより前記被検体の循環器病を治療することを含む方法。
- 原線維形成を含む被検体の線維性の疾患を治療する方法であって、前記被検体の原線維形成を阻害するために有効な請求項17に記載の薬学的組成物の量を前記被検体に投与して、これにより前記線維性の疾患を治療することを含む方法。
- 前記線維性の疾患が腎疾患である、請求項23記載の方法。
- 前記線維性の疾患が肝臓の疾患である、請求項23に記載の方法。
- 線維性の疾患が肺の疾患である、請求項23に記載の方法。
- 線維性の疾患が皮膚の病気である、請求項23に記載の方法。
- 線維性の疾患が眼の疾患である、請求項23に記載の方法。
- 高いストリンジェンシーの条件下でPAI-1をコードするmRNAとハイブリダイズし、かつ8〜40ヌクレオチドの間の長さである連続したヌクレオチドを含むオリゴヌクレオチド。
- 前記オリゴヌクレオチド内の少なくとも1つのヌクレオシド間結合が、ホスホロチオネート結合を含む、請求項29に記載のオリゴヌクレオチド。
- 前記ヌクレオチドが、少なくとも1つのデオキシリボヌクレオチドを含む、請求項29に記載のオリゴヌクレオチド。
- 前記ヌクレオチドが、少なくとも1つのリボヌクレオチドを含む、請求項29に記載のオリゴヌクレオチド。
- 前記PAI-1をコードするmRNAが、ヒトPAI-1をコードする、請求項29のオリゴヌクレオチド。
- 前記ヒトPAI-1をコードするmRNAが、配列番号:5に記載されている配列の連続したヌクレオチドを含む、請求項33に記載のオリゴヌクレオチド。
- 請求項29に記載のオリゴヌクレオチドおよび薬学的に許容されるキャリアを含む薬学的組成物。
- 被検体を治療する方法であって、前記被検体のPAI-1の発現を阻害するために有効な請求項29のオリゴヌクレオチドの量を前記被検体に投与して、これにより前記被検体を治療することを含む方法。
- 被検体の心筋細胞のアポトーシスを含む前記被検体の循環器病を治療する方法であって、前記被検体の心筋細胞のアポトーシスを阻害するために有効な請求項35の薬学的組成物の量を前記被検体に投与して、これにより循環器病を治療することを含む方法。
- 被検体の原線維形成を含む前記被検体の線維性の疾患を治療する方法であって、前記被検体の原線維形成を阻害するために有効な請求項35の薬学的組成物の量を前記被検体に投与してこれにより線維性の疾患を治療することを含む方法。
- 被検体の新内膜形成を含む前記被検体の循環器病を治療する方法であって、前記被検体の新内膜形成を阻害するために有効な請求項35の薬学的組成物の量を前記被検体に投与して、これにより被検体の循環器病を治療することを含む方法。
- 前記被検体がバルーン血管形成術を受けている、請求項22または39に記載の方法。
- 前記被検体がステント移植を受けている、請求項22または39に記載の方法。
- 前記循環器病が再狭窄である、請求項22または39に記載の方法。
- 被検体の血管疾患を治療する方法であって、前記疾患は、トロンビンまたはフィブリン産生の減少によって治療される疾患であり、該方法は、前記被検体の血管疾患を治療するために、PAI-1発現を阻害し、これによりトロンビンまたはフィブリン産生を減少させるために有効なPAI-1発現の阻害剤を投与することを含む方法。
- 前記触媒核酸が、ステント、足場を経て、静脈内に、経口的に、吸入によって、皮下に、直接の筋注投与によって、または遺伝子ベクターを介して投与される、請求項19に記載の方法。
- 前記薬学的組成物が、ステント、足場を経て、静脈内に、経口的に、吸入によって、皮下に、直接の筋注投与によって、または遺伝子ベクターを介して投与される、請求項20、21、22、23、37、38、または39のいずれか1項に記載の方法。
- 前記オリゴヌクレオチドが、ステント、足場を経て、静脈内に、経口的に、吸入によって、皮下に、直接の筋注投与によって、または遺伝子ベクターを介して投与される、請求項36記載の方法。
- 被検体の血管疾患を治療する方法であって、前記血管疾患は、PAI-1発現の阻害によって治療される疾患であり、該方法は、前記被検体のPAI-1発現を阻害するために有効なPAI-1発現の阻害剤を前記被検体に投与して、これにより前記被検体の血管疾患を治療する方法。
- 前記PAI-1発現の阻害剤がアンチセンス・オリゴヌクレオチド、抗体、触媒核酸、小分子、またはRNAiである、請求項43または47に記載の方法。
- 前記疾患が虚血性の疾患である、請求項43または47に記載の方法。
- 前記虚血性の疾患が末梢動脈疾患または脳血管障害である、請求項49に記載の方法。
- 被検体の心臓組織の新血管新生を誘導する方法であって、前記心臓のPAI-1の発現を阻害するために有効なPAI-1発現の阻害剤の量を前記被検体に投与して、これにより前記被検体の心臓組織の新血管新生を誘導ことを含む方法。
- 前記被検体が循環器病を患っている、請求項51記載の方法。
- 前記疾患が心筋梗塞、アンギナ、鬱血性心不全、末梢動脈疾患、または心筋の低酸素症である、請求項52に記載の方法。
- 被検体の組織の新血管新生を誘導する方法であって、前記被検体の組織のPAI-1の発現を阻害するために有効なPAI-1発現の阻害剤の量を前記被検体に投与して、これにより前記被検体の組織の新血管新生を誘導することを含む方法。
- 前記被検体が虚血性の疾患を患っている、請求項54に記載の方法。
- 前記疾患が虚血性の腎疾患、脳血管障害、脳卒中、または肝臓の疾患である、請求項55に記載の方法。
- PAI-1発現の阻害剤および薬学的に許容されるキャリアを含む薬学的組成物。
- 前記PAI-1発現の阻害剤が、触媒核酸、オリゴヌクレオチド、モノクローナル抗体、小分子、またはRNAiである、請求項57に記載の薬学的組成物。
- 被検体の循環器病を治療する方法であって、前記疾患は、被検体の心筋機能を改善することによって治療され、該方法は、心筋機能の改善を阻害する請求項58に記載の薬学的組成物の量を前記被検体に投与して、これにより前記被検体の循環器病を治療することを含む方法。
- 前記被検体に薬学的組成物を投与する前に、同時に、または後に薬剤を投与することをさらに含む、請求項59に記載の方法。
- 前記薬剤が、内皮前駆細胞、骨髄細胞、心臓前駆細胞、胚幹細胞、または脈理血液幹細胞である、請求項60記載の方法。
- 薬剤が、G-CSF、GM-CDF、SDF-1、IL-8、SCF、VEGF、FGF、またはGROファミリーケモカインである、請求項60に記載の方法。
- 被検体の組織の平滑筋細胞の増殖を阻害する方法であって、前記被検体の組織の平滑筋細胞の増殖を阻害するために有効な請求項58に記載の薬学的組成物の量を前記被検体に投与することを含む方法。
- 被検体の心臓においてトロンビンおよびフィブリン沈着を阻害する方法であって、前記被検体の心臓におけるトロンビンおよびフィブリン沈着を阻害するために前記被検体に有効な請求項58に記載の薬学的組成物の量を前記被検体に投与することを含む方法。
- 請求項63または64に記載の方法であって、内皮前駆細胞、骨髄細胞、心臓前駆細胞、胎生期、幹細胞、または脈理血液幹細胞を前記被検体に投与することをさらに含む方法。
- 前記薬学的組成物が、ステント、足場を経て、静脈内に、経口的に、吸入によって、皮下に、直接の筋注投与によって、または遺伝子ベクターを介して投与される、請求項59、63、または64に記載の方法。
- 被検体の組織におけるトロンビンおよびフィブリン沈着を阻害する方法であって、前記被検体の組織におけるトロンビンおよびフィブリン沈着を阻害するために前記被検体に有効な請求項58の薬学的組成物の量を投与することを含む方法。
- 前記被検体は、深部静脈血栓、肺塞栓症、腎疾患、冠状動脈梗塞、転移、炎症、播種性血管内血液凝固、アテローム性動脈硬化症、リウマチ様関節炎、糸球体腎炎、全身性エリテマトーデス、自己免疫性神経障害、肉芽腫症、または同種異系移植片拒絶反応に罹患している、請求項67に記載の方法。
- 被検体の感染性ショックを治療する方法であって、前記被検体の治療方法感染性ショックに有効な請求項58の薬学的組成物の量を前記被検体に投与することを含む方法。
- 血栓性疾患、血栓性障害、または止血性障害を患っている被検体を治療する方法であって、前記疾患または障害は、PAI-1の高い発現と関係する疾患または障害であり、該方法は、前記被検体のPAI-1発現を減少させるために有効な請求項58の薬学的組成物の量を前記被検体に投与して、これにより疾患を治療することを含む方法。
- 前記疾患または障害は、深部静脈血栓、肺塞栓症、腎性疾患、冠状動脈梗塞、転移、炎症、播種性血管内血液凝固、アテローム性動脈硬化症、リウマチ様関節炎、糸球体腎炎、全身性エリテマトーデス、自己免疫性の神経障害、肉芽腫症、または同種異系移植片拒絶反応である、請求項58記載の方法。
- 請求項70記載の方法であって、被検体血小板溶解薬または血小板溶解薬の活性化因子を投与することをさらに含む方法。
- 前記血小板溶解薬の活性化物質が、組織プラスミノーゲンアクチベーター、ウロキナーゼ、ストレプトキナーゼ、またはプロウロキナーゼである、請求項72に記載の方法。
- 請求項70または72に記載の方法であって、前記被検体に抗凝固薬を投与することをさらに含む方法。
- 前記抗凝固薬が、ヘパリン、ワルファリン、アスピリン、アニシンジオン、フェニンジオン(phenindone)、またはヒドロキシクマリンである、請求項74記載の方法。
- 前記被検体が哺乳類である、請求項19、20、21、22、23、36、37、38、39、43、47、51、54、59、63、64、67、69、または70に記載の方法。
- 前記哺乳類がヒトである、請求項76に記載の方法。
- PAI-1発現の阻害剤の治療的に有効な量および薬学的に許容されるキャリアを混合することを含む請求項57の薬学的組成物の方法。
- 心筋細胞の減少を含む被検体の心臓の障害を治療する方法であって、前記被検体の心臓内で心筋細胞増殖を引き起こすために有効なPAI-1発現の阻害剤の量を前記被検体に投与して、これにより前記障害を治療することを含む方法。
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MX2008016221A (es) | 2006-07-05 | 2009-02-23 | Catalyst Biosciences Inc | Métodos de selección de proteasa y proteasas identificadas por este medio. |
CN107630011A (zh) * | 2006-07-05 | 2018-01-26 | 催化剂生物科学公司 | 蛋白酶筛选方法及由此鉴别的蛋白酶 |
CN105148261A (zh) * | 2008-03-31 | 2015-12-16 | 苏州兰鼎生物制药有限公司 | 尿激酶原及尿激酶原变体在急性心肌梗塞易化经皮冠状动脉介入中的应用 |
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WO2001051085A1 (en) * | 2000-01-14 | 2001-07-19 | Tanox, Inc. | Use of antagonists of plasminogen activator inhibitor-1 (pai-1) for the treatment of asthma and chronic obstructive pulmonary disease |
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JP2011509093A (ja) * | 2008-01-09 | 2011-03-24 | イントレキソン コーポレーション | Pai−1機能の治療的阻害因子およびその使用法 |
JP2012135307A (ja) * | 2008-01-09 | 2012-07-19 | Intrexon Corp | Pai−1機能の治療的阻害因子およびその使用法 |
US8828686B2 (en) | 2008-01-09 | 2014-09-09 | Intrexon Corporation | Polynucleotides encoding therapeutic inhibitors of PAI-1 |
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EP1501948A1 (en) | 2005-02-02 |
DE60333747D1 (de) | 2010-09-23 |
US7662794B2 (en) | 2010-02-16 |
WO2003091456A1 (en) | 2003-11-06 |
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