JP2022505468A - 可溶性細胞外マトリックス組成物および血管内送達のための方法 - Google Patents
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Abstract
Description
本出願は、2018年10月25日に提出された米国仮出願第62/750,303号の優先権の利益を主張し、その出願は参照により本明細書に組み込まれる。
本発明は、国立衛生研究所(NIH)によって授与された助成金番号HL113468の下で政府の支援を受けてなされた。政府は本発明に特定の権利を有する。
a.ペプシンなどの酸性プロテアーゼで、組織から調製された脱細胞化ECMを部分的または完全に消化することと、
b.消化されたECM材料をpH7.0~8.0に中和することと、
c.可溶性および不溶性画分を生成するために液体ECM(プレゲル溶液)を処理することと、
d.可溶性ECM組成物を得るために、不溶性画分の少なくとも一部を可溶性画分から分離することと、を含む、方法を提供する。
心筋マトリックス(MM)の配合物は、以前に記載されたプロトコルに基づいて生成することができる(図1)[3]。端的に述べると、ブタ(約30~45kg)から新鮮な心臓を採取し、LV心筋を単離する。主要な血管および結合組織を除去し、残りの組織を5mm3未満の小片に切断する(図1A)。組織が完全に白くなるまで4~5日間、1%(w/v)ドデシル硫酸ナトリウム(SDS)中で組織を脱細胞化し、その後さらに1日水ですすいで残留SDSを除去する(図1B)。材料を凍結乾燥し、微粉末に粉砕し(図1C)、続いて48時間部分的に酵素消化する。次いで、材料を中和し、インビボ条件に一致するように緩衝し、熱的に誘発されるゲル化が可能なMM(図1D)を得る。
SolMMとヒト血液試料(n=4)との間の相互作用を、ヒト全血または多血小板血漿に対して異なる希釈(1:1、1:2、1:10)のSolMMで評価する。1:1は、血液とSolMMとの間の可能な限り高い比率を表し、1:10は、冠状血管系の体積流量および意図される注入速度(1mL/分)に基づく生理学的に適切な希釈を表す。血液適合性は、MMについて以前に記載されたように評価する[4]。赤血球の凝集は、自己血漿でヘマトクリット値を45%に調整した後、Myrenne凝集計(Myrenne GmbH)でサンプリングしてから4時間以内に行う。凝集は、うっ滞(M0)または低せん断速度(3Hz;M1)の後に評価し、吸光度(800nm)は5秒間測定する。同様に、血小板凝集は、ルミ凝集計(Chrono-log)で単離された多血小板血漿を用いて測定する。多血小板血漿に対する試料に上記と同じ希釈率を使用して、高濃度の凝固カスケードアゴニスト(アデノシン二リン酸、エピネフリン、およびコラーゲン)を添加し(1:200~1:1000希釈)、血小板凝集を吸光度により測定する(600~620nm)。
MIのSprague Dawleyラット(225~250g)の心筋虚血再灌流モデルを使用して、左冠状動脈を45分間閉塞させた後、再灌流する。再灌流後5分以内に、大動脈を約15秒間クランプして冠動脈内注入をシミュレートし、200μlのSolMMを6、10、または14mg/mLの濃度でLV内腔に注入する。これにより、材料が冠状動脈内に強制的に押し込まれ、梗塞した心筋に分布される[12]。1時間以内に非ゲル化材料が心臓から除去されるため、注射の60分後に心臓(濃度当たりn=2)を単離し、材料が最初に分布され、次いで心臓に保持されるかどうかを判断する[5]。SolMMは、Alexa Fluor(商標)568 N-ヒドロキシスクシンイミジルエステル(Invitrogen)と結合して蛍光の検出および分析を可能にする。注入後6、12、および24時間、2、3、4、および5日、ならびに1週間の時点(時点当たりn=2~3)で、最適な濃度での材料の保持を調べて分解を評価する。対照としての役割を果たすように、生理食塩水(時点当たりn=3)を非結合Alexa Fluor(商標)568と混合する。OCT Tissue-Tekコンパウンド中で心臓を新鮮凍結し、等間隔の16の領域(領域間が約300μm)になるよう短軸方向に薄片化し、領域当たり4つのスライドを2通り作り、切片当たり10μmとした。梗塞を確認するためのH&Eに領域当たり1つのスライドを使用し、SolMMの蛍光分析に領域当たり1つのスライドを使用する。
心筋梗塞後、バルーン付き注入用カテーテルを使用した標的化送達のために、心臓の血管(例えば、左前下行枝または左主幹動脈)を通して細胞外マトリックスを注入した。図4は、バルーン付き注入用カテーテルを使用したブタ虚血再灌流モデルにおける冠動脈内注入の1時間後の可溶性心筋マトリックス(SolMM)の分布および保持を示す。図4左は、梗塞したブタの心臓の肉眼的短軸組織像を示す。梗塞が青色グレースケールで囲われている。図4右は、梗塞した心筋全体にSolMMミクロゲルを表示する梗塞した心筋を赤色グレースケールチャネルで示している。
図6は、心筋梗塞モデルにおけるマトリックス注入後の梗塞細動脈密度の増加を示す。ラット虚血再灌流モデルに注入した5週間後に梗塞を画像化した。細動脈は、α平滑筋アクチンとイソレクチンとの共染色によって同定し、ImageJにおいて手動で追跡した。血管新生経路のアップレギュレーションを図6に示す。
図7は、心筋梗塞モデルにおけるマトリックス注入後の心筋細胞アポトーシスの減少を示す。梗塞および梗塞境界ゾーンを、心筋細胞についてα-アクチニンで染色し、アポトーシスについて切断されたカスパーゼ3で染色した。アポトーシス心筋細胞は、ImageJにおいて手動でカウントした。アポトーシスの減少は、他の細胞タイプにまで及ぶ可能性があるが、内皮細胞、免疫細胞、線維芽細胞、ニューロン、および(心筋)筋細胞に限定されない。アポトーシス/壊死経路の減少を図9に示す。アップレギュレートされた活性酸素種(ROS)代謝経路が図8に示されるように、アポトーシスの減少はROS代謝の増加によって説明され得る。
虚血性損傷およびマトリックス注入に続いて、可溶性マトリックスが小血管(毛細血管/内皮細胞)の内腔をコーティングすることが観察された。図10は、可溶性マトリックス(赤色グレースケール)でコーティングされた内皮細胞(緑色グレースケール)の内腔を示す。マトリックスが内腔を閉塞しないことに留意されたい。追加的に、図11は、可溶性マトリックスが大血管の内皮細胞と重複しているが、内腔を閉塞していないことを示す。注入後24時間まで共焦点顕微鏡を使用して心臓を画像化し、心筋梗塞をシミュレートした。
可溶性細胞外マトリックス組成物は、成長因子、マイクロRNA、および他の潜在的な薬物または治療薬のための潜在的な結合ドメインを有する。注入可能なマトリックスは注入後に組織内でゲル化し得るため、治療薬の徐放に使用することができる。
図14は、1:50希釈(それぞれ1.0mg/mlおよび0.6mg/ml)での可溶性マトリックス(SolMM)および完全マトリックス(MM)の動的光散乱データを示しており、可溶性マトリックス粒子が直径100nm未満であるのに対し、完全なマトリックスはより大きな粒子を有することを示している。
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Claims (32)
- 可溶性細胞外マトリックス(ECM)組成物を調製する方法であって、
a.脱細胞化ECM材料を酸性プロテアーゼで消化することと、
b.前記消化されたECM材料を液体中でpH7.0~8.0に中和することと、
c.可溶性および不溶性画分を生成するために前記液体ECMを処理することと、
d.可溶性ECM組成物を得るために、前記可溶性画分の少なくとも一部を前記不溶性画分から分離することと、を含む、方法。 - 前記可溶性および不溶性画分を生成するために前記液体ECMを処理することは、遠心分離によって行われる、請求項1に記載の方法。
- 前記可溶性および不溶性画分を生成するために前記液体ECMを処理することは、透析または濾過によって行われる、請求項1に記載の方法。
- 前記分離は、250nm以下のサイズの除外フィルタを用いて行われる、請求項1に記載の方法。
- 前記可溶性ECM組成物は、さらに凍結乾燥および再水和される、請求項1に記載の方法。
- 固体ECM材料の少なくとも一部が除去された、脱細胞化、消化および中和された組織を含む可溶性ECM組成物であって、前記可溶性ECM組成物は、250nmサイズの除外フィルタを通過する、可溶性ECM組成物。
- 前記組成物は、血管内注入のために配合される、請求項6に記載の可溶性ECM組成物。
- 前記組成物は、室温で液体であり、インビボでの注入または注射後にゲルを形成する、請求項6に記載の可溶性ECM組成物。
- 前記組成物は、室温で液体であり、インビボでの注入または注射後に損傷した血管を裏打ちするコーティングを形成する、請求項6に記載の可溶性ECM組成物。
- 前記組成物は、室温で液体であり、インビボでの注入または注射後に内皮細胞間の細孔を充填する、請求項6に記載の可溶性ECM組成物。
- ヒト、動物、胚、または胎児の組織に由来する、請求項6に記載の可溶性ECM組成物。
- 心臓、脳、膀胱、小腸、または骨格筋組織、腎臓、肝臓、肺、および血管に由来する、請求項6に記載の可溶性ECM組成物。
- 組織修復を促進するために対象を治療する方法であって、それを必要とする対象に、請求項6に記載の可溶性ECM組成物の有効量の注入液を投与することを含む、方法。
- 前記注入液は、カテーテルを介して、静脈内に、または血管内に送達される、請求項13に記載の方法。
- インビボで送達される場合、前記可溶性ECM組成物は組織内でゲルを形成する、請求項13に記載の方法。
- 前記可溶性ECM組成物は、投与前に、グルタルアルデヒド、ホルムアルデヒド、ビス-NHS分子、または他の架橋剤で架橋される、請求項13に記載の方法。
- 前記可溶性ECM組成物は、投与前に、細胞、ペプチド、タンパク質、DNA、薬物、ナノ粒子、栄養素、生存促進添加剤、プロテオグリカン、および/またはグリコサミノグリカンと組み合わされる、請求項13に記載の方法。
- 前記可溶性ECM組成物は、投与前に、合成ポリマーまたは生物学的に誘導された材料と組み合わされるおよび/または架橋される、請求項13に記載の方法。
- 前記可溶性ECM組成物は、前記対象において、内因性の細胞内殖、血管新生、および再生を引き起こす、請求項13に記載の方法。
- 前記可溶性ECM組成物は、前記対象において、細胞の生存を促進し、炎症を軽減する、請求項13に記載の方法。
- 急性心筋梗塞を治療するための方法であって、固形ECM材料の少なくとも一部が除去された、脱細胞化、消化および中和された組織を含む有効量の可溶性ECM組成物を、必要とする対象に注射または注入することを含む、方法。
- 前記組成物は、血管内に送達される、請求項21に記載の方法。
- 前記組成物は、バルーン付き注入用カテーテルを用いて送達される、請求項21に記載の方法。
- 前記組成物は、送達後に組織内でゲル形態に移行する、請求項21に記載の方法。
- 前記組成物は、室温で液体であり、送達後に梗塞血管を裏打ちするコーティングを形成する、請求項21に記載の方法。
- 前記組成物は、室温で液体であり、送達後に梗塞内皮細胞間の細孔を充填する、請求項21に記載の方法。
- 前記組成物は、注射または注入後1~14日以内に分解する、請求項21に記載の方法。
- 前記組成物の注射または注入は、前記対象によって持続される心筋への損傷を修復する、請求項21に記載の方法。
- 前記組成物の注射または注入は、前記対象の虚血によって引き起こされた損傷を修復する、請求項21に記載の方法。
- 前記有効量は、血流を増加させる、生存可能な組織量を増加させる、または前記対象の前記注射もしくは注入の領域に新しい血管形成を誘発する量である、請求項21に記載の方法。
- 内皮細胞損傷および/または機能不全を治療する方法であって、固形ECM材料の少なくとも一部が除去された、脱細胞化、消化および中和された組織を含む有効量の可溶性ECM組成物を、必要とする対象に注射または注入することを含む、方法。
- 前記有効量は、内皮細胞の生存、増殖、もしくは血管作用を促進し、かつ/または炎症、アポトーシス、活性酸素種の損傷、もしくは漏出性血管系を減少させる、請求項31に記載の方法。
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