JP2023052764A - 急性虚血性脳卒中の処置のための方法及び医薬組成物 - Google Patents
急性虚血性脳卒中の処置のための方法及び医薬組成物 Download PDFInfo
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Abstract
Description
急性虚血性脳卒中(AIS)は、脳の区画への十分な血流が突然遮断されることであり、通常は脳に血液を供給している動脈の1つにつまっている又は形成している血栓又は他の塞栓により引き起こされる。遮断がすぐに取り除かれない場合、虚血は、永続的な神経障害又は死亡に至る場合がある。組み換え組織型プラスミノーゲンアクチベーター(t-PA;アルテプラーゼ、Actilyse(登録商標)、Boehringer Ingelheim)の静脈内(IV)投与は、AISにおいて有効性が確認されている唯一の薬物療法である。この処置は、早期再疎通の点で効率が低い。2015年以来、この処置は、近位頭蓋内動脈閉塞の場合の早期再疎通率における増加及び3ヶ月目の機能的転帰の有意な改善を可能にする血管内処置(EVT)の実現に関連する。AIS処置についての時間枠は、IV t-PA注入について4,5時間以内及びEVTについて6時間以内である。この時間内であっても、症状の発生と処置との間の時間が短いほど結果が良好であるという強力な証拠がある。AISのEVTは、ステントリトリーバー又は直接吸引カテーテルなどの血栓除去デバイスを用いた血栓の機械的除去にある。
好中球細胞外トラップ(NETs)は、活性化好中球により生成されるヒストン及び顆粒タンパク質で装飾されたDNA細胞外ネットワークである。NETsは、血栓症の主なトリガー及び構造因子として特定されている。本発明者らの目的は、急性虚血性脳卒中(AIS)の患者における血管内療法の間に回収される血栓中のNETsの存在及びt-PA誘導血栓溶解に対するそれらの影響を評価することであった。したがって、本発明者らは、血管内療法で処置された108人のAIS患者からの血栓を分析した。血栓は、ヘマトキシリン/エオジン染色、免疫染色、及びエクスビボ酵素アッセイ法により特徴付けられた。追加的に、本発明者らは、AIS血栓の血栓溶解に対するデオキシリボヌクレアーゼ1(DNAse 1)の影響をエクスビボで評価した。組織学的分析により、NETsが全てのAIS血栓の組成に、特にそれらの外層における組成に寄与したことが明らかになった。血栓NETs含量の定量測定は、臨床転帰又はAISの病理発生と関連しなかったが、血管内療法手技の長さ及びデバイスのパス数と有意に相関した。エクスビボで、組み換えDNAse 1は、t-PA誘導血栓溶解を促進したのに対し、DNAse 1単独は無効であった。この研究は、血栓のNETs含量が、その原因にかかわらず、機械的アプローチ又は静脈内t-PAによる薬理的アプローチを含む再灌流の抵抗性の原因になり得ることを示唆している。これらの結果は、また、t-PA及びDNAse 1に関連する併用療法が、t-PAの有効性を可能にする相乗作用を有し得ることを示唆している。
- 配列番号:1又は配列番号:2の125位のプロリンのアルギニンによる置換、
- 配列番号:1若しくは配列番号:2中のN末端のフィンガードメインの欠失及び/若しくはEGF様ドメインの欠失、並びに/又は配列番号:1若しくは配列番号:2の117位のアスパラギンのグルタミンによる置換、
- 配列番号:1若しくは配列番号:2の103位のトレオニンのアスパラギンによる置換、及び/又は配列番号:1若しくは配列番号:2の117位のアスパラギンのグルタミンによる置換、及び/又は配列番号:1の296~299位のリシン-ヒスチジン-アルギニン-アルギニン(KHRR)のアラニン-アラニン-アラニン-アラニン(AAAA)による置換、
- 配列番号:1又は配列番号:2の84位のシステインのセリンによる置換、
- 配列番号:1若しくは配列番号:2の275位のアルギニンのグルタミン酸若しくはグリシンによる置換、及び/又は配列番号:1若しくは配列番号:2中のクリングル1ドメインの欠失
のうち少なくとも1つを含む。
試料の選択
本発明者らの施設で2015年12月と2016年12月との間に血管内療法(EVT)により処置され、血栓回収が成功した患者を本研究に登録した。地域の倫理委員会がこの研究プロトコールを承認した。
構造化質問票(ETISレジストリ、虚血性脳卒中における血管内処置)を使用して、患者の人口統計、血管危険因子、画像所見、処置前の生命徴候、AISの重症度及び臨床転帰を前向きに収集した。TOAST分類を使用して脳卒中の原因を分類した。
最初の例では、インターベンション医師の自由裁量で、ステントリトリーバー又は直接吸引ファーストパス技術(direct aspiration first path technique)を使用するEVT手技を選択した。詳細な技術的手技は、以前に刊行されている。1
急性虚血性脳卒中(AIS)の血栓をEVTの終わりに収集した。それらを-20℃で直ちに凍結し、次に-80℃で保存し、かつ/又は3,7%パラホルムアルデヒド中で固定し、次にパラフィン中に包埋した。108人の患者を含めた。74人の患者からの血栓を溶解アッセイ法のため(n=24)及び/又はエンドヌクレアーゼ処置後のNE放出の測定により評価されるNETs含量の決定のために使用した。NE抗原(n=72)及び/又は活性(n=23)の測定によりNEの放出を定量した。34人の患者からの血栓をパラホルムアルデヒド中で固定し、免疫組織分析のために使用した。
脱パラフィン後に、組織切片を透過処理し、洗浄し、MPOに対する一次抗体(ウサギ抗ヒトMPO抗体、A0398、Dako)、シトルリン化ヒストンH4(ウサギ抗ヒトヒストンH4(シトルリン3)抗体、07-596、Millipore)と共にインキュベートし、続いて蛍光二次抗体と共にインキュベートし、DAPI(Sigma- Aldrich)で対比染色した。各AIS血栓にヘマトキシリン/エオシン(H&E)染色も行った。
市販のNETsアッセイキット(Cayman chemical)を使用した。このアッセイキットは、エンドヌクレアーゼと一緒のインキュベーションの前及び後の組織上清中の好中球エラスターゼ活性を測定することにある。放出された好中球エラスターゼは、細胞外DNA関連好中球エラスターゼに対応する。AIS血栓のNETs含量を定量するために、ヒト好中球エラスターゼELISAキット(HycultBiotech)を使用して、エンドヌクレアーゼ処置後に回収された血栓の上清中の好中球エラスターゼ抗原を測定した。
以下のプロトコールは、Mangoldら(2)を改作したものであった。簡潔には、凍結AIS血栓を解糖し、2つの等しい部分に分割し、500rpm及び37℃のサーモミキサー上で組み換えt-PA(1μg/mL, Actilyse, Boehringer Ingelheim, Ingelheim am Rhein, Germany)及び/又は組み換えDNAse 1(100IE/ml, プルモザイム, Roche, Basel, Switzerland)の存在下のPBS中でインキュベートした。処置の開始の前並びに10、30及び60分後に超精密天秤を使用して血栓の重量を測定した。血栓の溶解をベースラインの血栓重量に対するパーセントとして表現した。
ノンパラメトリック分散分析(Kruskal-Wallis)に続く、対応のあるデータの比較のためのWilcoxon順位和検定又は対応のないデータの比較のためのMann-WhitneyのU検定を使用してデータを解析した。連続変数について平均±SDとして、質的変数について数字(パーセンテージ)として結果を提示する。統計解析について、PrismGraph 4.0ソフトウェア(GraphPad Software, San Diego, CA)を使用した。P<0.05の値を統計的に有意と見なした。
患者の特徴
本発明者らは、本研究に2015年12月と2016年12月との間の108人の患者を含めた。患者の特徴を表Iに示す。これらの特徴は、最近公表されたEVT治験の特徴に類似している。
H&E染色後のAIS血栓の形態計測分析により、調査されたすべての血栓中に多数の多形核細胞が存在することが明らかとなった。NETsを示唆している細胞外核酸のストランドが、組織学的に分析された34個の血栓すべてに、特にそれらの表層に見いだされた(データは示さず)。
エンドヌクレアーゼで処置された血栓(n=72)から放出されるNE抗原を測定することにより血栓好中球由来細胞外DNA含量を定量した。NETs含量と脳卒中の原因、3ヶ月の機能的帰結又は最終TICIスコアとの間に有意な相関はなかった(図4A)。IVのt-PAで以前に処置された患者からのNETsの血栓含量は、IV t-PA療法を受けなかった患者からの血栓と比較して有意に低減した(図4B)。最終的に、NETs含量は、血管内手技の長さ及びデバイスのパス数と正の相関を示した(図4C~D)。
DNAse 1によるNETsの標的化が血栓溶解を増強することができるかどうか試験するために、本発明者らは、24個のAIS血栓においてエクスビボ溶解アッセイ法を行った。第1の実験で、本発明者らは、t-PA単独に対してt-PA+DNAse 1を比較した(n=13)。DNAse 1をt-PAに添加することは、エクスビボ血栓溶解を有意に促進した。第2の実験において、本発明者らは、DNAse 1単独をt-PA+DNAse 1に対して比較した(n=11)。DNAse 1単独は、有意な血栓溶解を誘導するのに無効であった(図5A~B)。
本発明者らの研究は、(1)脳卒中の原因に関係なく、すべてのAIS血栓がNETsを含有すること、(2)NETsが、AIS血栓の外層に主に局在すること、(3)NETs含量が、血管内手技の長さ及びデバイスのパス数と関連すること、(4)t-PA及びDNAse 1の同時投与が、t-PA又はDNAse 1単独と比較してエクスビボ血栓溶解を促進することを示している。
NETsは、少なくとも部分的に、血栓t-PA抵抗性を担う足場を形成する。本発明者らのデータは、DNAse 1注入がAISにおけるIVのt-PA誘導血栓溶解の有効性を改善するための相乗作用を有し得るという概念を支持している。
Claims (20)
- AISの処置を必要とする患者におけるその処置における使用のための、t-PA及びDNAseを含む組み合わせ。
- t-PAが、組み換えt-PAである、請求項1記載の組み合わせ。
- t-PAが、天然型t-PAの酵素活性又は線維素溶解活性を保持する、天然型t-PAの修飾型である、請求項1又は請求項2記載の組み合わせ。
- t-PAが、野生型tPAのThr103がAsnに変更され(T103N)、野生型tPAのAsn117がGlnに変更され(N117Q)、野生型tPAのLys-His-Arg-Arg 296-299がAla-Ala-Ala-Alaに変更されている、天然型t-PAの修飾型である、請求項1~3のいずれか一項記載の組み合わせ。
- t-PAが、アルテプラーゼ又はテネクテプラーゼである、請求項1~4のいずれか一項記載の組み合わせ。
- DNAseが、DNAse 1である、請求項1~5のいずれか一項記載の組み合わせ。
- DNAseが、組み換え型である、請求項1~6のいずれか一項記載の組み合わせ。
- DNAseが、ヒト由来である、請求項1~7のいずれか一項記載の組み合わせ。
- DNAseが、ドルナーゼ又はプルモザイムである、請求項1~8のいずれか一項記載の組み合わせ。
- 急性虚血性脳卒中(AIS)の処置を必要とする患者におけるAISを処置する方法であって、患者にt-PAとDNAseとの治療的に有効な組み合わせを投与することを含み、ここで、組み合わせの投与が、t-PA単独の投与と比べて増強された治療有効性を生じる方法。
- AISを患う患者に処置レジメンの部分として投与されるt-PAの効力を増強するための方法であって、患者にDNAseと組み合わせた薬学的有効量のt-PAを投与することを含む方法。
- AISを患う患者における閉塞した頭蓋内動脈の再疎通を達成する方法であって、患者にt-PAと組み換えDNAseとの治療的に有効な組み合わせを投与することを含む方法。
- t-PAが、組み換えt-PAである、請求項10~12のいずれか一項記載の方法。
- t-PAが、天然型t-PAの酵素活性又は線維素溶解活性を保持する、天然型t-PAの修飾型である、請求項10~13のいずれか一項記載の方法。
- t-PAが、野生型tPAのThr103がAsnに変更され(T103N)、野生型tPAのAsn117がGlnに変更され(N117Q)、野生型tPAのLys-His-Arg-Arg 296-299が、Ala-Ala-Ala-Alaに変更されている、天然型t-PAの修飾型である、請求項10~14のいずれか一項記載の方法。
- t-PAが、アルテプラーゼ又はテネクテプラーゼである、請求項10~15のいずれか一項記載の方法。
- DNAseが、DNAse 1である、請求項10~16のいずれか一項記載の方法。
- DNAseが、組み換え型である、請求項10~17のいずれか一項記載の方法。
- DNAseが、ヒト由来である、請求項10~18のいずれか一項記載の方法。
- DNAseが、ドルナーゼ又はプルモザイムである、請求項10~19のいずれか一項記載の方法。
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