JP2017536127A - 炎症性疾患を治療するためのカプセル化幹細胞 - Google Patents
炎症性疾患を治療するためのカプセル化幹細胞 Download PDFInfo
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Abstract
Description
本明細書で用いられるとき、以下の用語の各々は、このセクション中でそれに関連した意味を有する。
MSC細胞培養
hMSCは、テキサスA&M大学(Texas A&M University)から購入した。細胞を10%MSC限定FCS、2ng/mlのL−グルタミン酸(L−glut)および1ng/mlのbFGFを添加したα−MEM(完全培地)中で増殖させた。MSCをファルコンフラスコ内に5,000細胞/cm2で播種し、培地を4日ごとに変更した。
マイクロカプセルへのMSCのマイクロカプセル化
アルギン酸溶液(2.5%)を、65℃の温度で加熱した磁気撹拌プレートを用いて、2.5gのアルギン酸ナトリウム(Pronova UP LVG、G含量:>60%、FMC Biopolymer Novamatrix)を100mLのα−MEMに溶解することにより調製した。次に、45μmのシリンジフィルター(Fisher Scientific,Pittsburg,PA)を用いて溶液を濾過した。マイクロカプセル内に細胞をカプセル化するため、0.9mLの2.5%アルギン酸溶液を、6×107個の細胞/mLの密度を有するMSC懸濁液の0.1mLの一定分量と混合し、6×106個の細胞/mLの最終細胞密度を得て、10mLのシリンジに移し、シリンジポンプ(KD Scientific,MA)に接続した。アルギン酸マイクロカプセルを、5mL/時間の流速および6.4kVの印加電圧で、PE−00940針(Nisco,Zurich,Switzerland)を用いる静電ビーズ発生器を用いて作製した。マイクロカプセルを、145mMのNaClおよび10mMのMOPSを含有する200mLのCaCl2槽(100mM)に押し出し(すべてはSigma−Aldrichから入手)、室温で10分間重合しておいた。管の底に定着させたマイクロカプセルおよび溶液をPBS中の0.05%(w/v)ポリ−L−リジン(Sigma Aldrich,USA)と交換し、10分間インキュベートした。ポリ−L−リジン溶液を除去し、マイクロカプセルを洗浄するため、ヘペス溶液と交換した。ヘペスを除去し、マイクロカプセル(図1A)を5mLの完全培地に再懸濁した。
インビトロでのマイクロカプセル内のMSCの生存度についてのアッセイ
カルセインおよびエチジウムホモ二量体アッセイ(Molecular Probes,USA)を用いて、カプセル内のMSC生存度を評価した(Maguire et al.,2007)。6.38μmの間隔でアルギン酸カプセルの断面画像を得るため、マイクロカプセルを共焦点顕微鏡(Zeiss 510 LSM)で画像化した(図1A、図1B)。次に、定量化のため、断面を単一面画像にコンパイルした。(緑色)の生細胞および赤色の死細胞を黒色および白色画像に変換した(各々、図1Aおよび図1B)。ImageJソフトウェア上で細胞カウンタープラグインを用いて生細胞および死細胞を計数し、生細胞/カプセルのパーセントは、生細胞数/(すべての生細胞数+死細胞数)であった。
マイクロカプセルのサイズについてのアッセイ
カプセルの明視野画像(図1C)を、ImageJ画像分析ソフトウェアを用いて直径を測定するのに用いて、平均を計算した。
カプセル注射の効率および再現性についてのアッセイ
内径が0.8mmの薄壁針(20ゲージ、NIPRO)を通じてeMSCを注射する効率および再現性を、IPマウス注射について分析した。20ゲージ針を用いたが、より狭い直径を有する、より高いゲージを有する針がカプセルの再現性のある駆出ができなかったためである。本発明者は、マウスへのIP注射後に管内およびシリンジ内に残存する数として注射されないカプセルの数を測定した。注射後、各管の内容物を組織培養皿に移し、カプセルの総数を明視野顕微鏡を用いて計数した(この画分を「管内残存」と称した)。針を取り付けたシリンジを生理食塩水で洗浄し、組織培養皿に移し、カプセルの総数を計数した(この画分を「シリンジ内残存」と称した)。「注射されない」カプセルと併せた総数を注射用に調製した全体(1600カプセルであった)から差し引いたが、その差が「注射された」カプセルの算出数である。平均「%注射」は、注射の効率を表す、注射されたものの平均数/1600として計算した(図5)。SDは標準偏差である。
マイクロカプセルによる敗血症の治療
敗血症は、マウスにおいて、盲腸の結紮および穿刺(CLP)によって誘導した。成体C57BL/6Jマウス(8〜12週齢)は、(Csoka et al.,FASEB J.29:25−36,2015)に記載のように、ペントバルビタールの腹腔内注射(50mg/kg)で麻酔した。盲腸を隣接する腸に曝露できるように、無菌条件下で、2cm正中線開腹手術を実施した。盲腸の約3分の2を3.0絹縫合で堅く結紮し、盲腸の結紮部分を20ゲージ針(BD Biosciences)で2回(徹底的に)穿孔した。その後、小量の便を穿孔部位を通して押し出すため、結紮した盲腸を緩やかに圧迫し、次に腹膜腔に戻した。開腹手術を4.0絹縫合を用いて二層に閉じた。手術後、すべてのマウスを皮下注射した1mlの生理食塩水で蘇生し、食料と水への自由なアクセスを伴うそれらのケージに戻した。CLPの1時間後、生理食塩水またはMSCマイクロカプセルを、1mlのシリンジに取り付けた薄壁20G針(内径=0.8mm,NIPRO)を用いて腹腔内注射した。CLP手術から16時間後、マウスをペントバルビタールで再麻酔し(50mg/kg腹腔内)、血液および腹膜洗浄物を収集した。
CLP誘導性敗血症における細菌のレベルに対するMSCマイクロカプセルの効果
約140,000個の生MSC/マウスを含有するマイクロカプセルを、CLPから1時間後と16時間後、マウスに腹腔内注射し、実施例6に記載のように血液および腹膜洗浄液を収集した。血液または腹膜洗浄液を滅菌生理食塩水で連続希釈した。50μLの各希釈物を無菌的に蒔き、トリプチカーゼ血液寒天プレート(BD Biosciences)上、37℃で培養した。24時間のインキュベーション後、細菌コロニーの数を計数した。細菌/培養物の数は、血液または腹膜洗浄液のCFU/mLとして表す(図2)。
敗血症マウス由来のマウスサイトカインに対するMSCマイクロカプセルの効果
実施例6に記載のように収集した血液(図3)および腹膜洗浄液(図4)の中のIL−10、IL−6、TNFα、IL−1β、MCP−1、およびMCP−2の濃度を、市販のELISAキット(R&D Systems,Minneapolis,MN,USA)を用いて製造業者の使用説明書に従って測定した。
敗血症マウスからのMSCマイクロカプセルの回収
MSCマイクロカプセルを、16時間後、注射したCLPマウスの腹膜洗浄液から回収した。液は1.5mlのマイクロチューブ内に収集し、2分後、液を除去し、沈殿物とともに約0.05mLが残存した。マイクロカプセルを含有する沈殿物を1mLのPBSで2回洗浄し、培地に再懸濁した。生細胞および死細胞/カプセルの数を、実施例3における生存度アッセイを用いて測定した(図6)。
CLPマウスから回収したMSCマイクロカプセルからのヒトIL−6の分泌
培養下で維持されたか、または実施例9と同様に注射の16時間後にCLPマウスから回収された約5,000個の細胞を含有するマイクロカプセルを、培地中で24時間インキュベートした。培地を収集し、ヒトIL−6用のElisaアッセイ(BioRad)を用いてヒトIL−6の分泌を測定するために用いた(図7)。
MSCマイクロカプセルからのPGE2の分泌
培養下で維持された約5,000個の細胞を含有するマイクロカプセルを、培地中で24時間インキュベートした。培地を収集し、(BioRad)用のElisaアッセイを用いてPGE2の分泌を測定するために用いた(図8)。
Claims (33)
- 幹細胞の単離された集団であって、カプセル化幹細胞の前記単離された集団が、少なくとも1つの治療関連タンパク質をインビトロよりも少なくとも2倍多くインビボで分泌する、幹細胞の単離された集団。
- 前記幹細胞が間葉系幹細胞(MSC)である、請求項1に記載の幹細胞の単離された集団。
- 骨髄、脂肪組織、臍帯、胎盤、間葉系前駆細胞(MPC)または多能性成体前駆細胞(MAPC)に由来する、請求項2に記載の間葉系幹細胞。
- 前記少なくとも1つの治療関連タンパク質が、上皮成長因子(EGF)、線維芽細胞成長因子(FGF)、血小板由来成長因子(PDGF)、トランスフォーミング増殖因子−B(TGF−B)、血管内皮増殖因子(VEGF)、肝細胞増殖因子(HGF)、インスリン成長因子−1(IGF−1)、アンジオポエチン−1(Ang−1)、ケラチノサイト成長因子(KGF)、および間質細胞由来因子−1(SDF−1)、ならびにこれらの組み合わせからなる群から選択される、請求項1に記載の幹細胞の単離された集団。
- 前記少なくとも1つの治療関連タンパク質が、腫瘍壊死因子誘導性遺伝子6タンパク質(TSG−6)、インターロイキン4(IL−4)、インターロイキン5(IL−5)、インターロイキン6(IL−6)、インターロイキン10(IL−10)、インターロイキン33(IL−33)、インターロイキン−1受容体拮抗剤(IL−1RA)、ガレクチン−1、ガレクチン−3、アディポネクチン、レゾルビンD1(RvD1)またはレゾルビンE1(RvE1)からなる群から選択される、請求項1に記載の幹細胞の単離された集団。
- 前記少なくとも1つの治療関連タンパク質が、プロスタグランジン、好ましくはプロスタグランジンE2(PGE2)からなる群から選択される、請求項1に記載の幹細胞の単離された集団。
- 前記カプセル化幹細胞の治療効果が、疾患に起因する損傷組織を修復し、疾患の進行を遅延させるか、または疾患の症状を軽減する、請求項1に記載の幹細胞の単離された集団。
- 敗血症、急性肺損傷(ALI)、急性呼吸促迫症候群(ARDS)、重症虚血肢(CLI)、脊髄損傷(SCI)、外傷性脳損傷(TBI)、エボラ、急性肺損傷(ALI)、および急性呼吸促迫症候群(ARDS)から選択される、請求項7に記載の疾患。
- 炎症性腸疾患(IBD)、クローン病、関節リウマチ(RA)、うっ血性心不全、筋萎縮性側索硬化症(ALS)、糖尿病性網膜症(DR)、黄斑変性症(MD)、パーキンソン病(PD)、多発性硬化症(MS)、1型糖尿病および2型糖尿病のリストから選択される、請求項7に記載の疾患。
- siRNA、miRNA、またはdsRNA分子を発現する外来性DNA配列を含む幹細胞の単離された集団であって、前記カプセル化幹細胞が、前記siRNA、miRNA、またはdsRNAポリヌクレオチドを、微小胞、エキソソーム、または細胞突起を介して標的細胞に送達する、幹細胞の単離された集団。
- カプセル化幹細胞の前記単離された集団が、前記siRNA、miRNA、またはdsRNAポリヌクレオチドの標的細胞への微小胞、エキソソームまたは細胞突起を介する導入に適した条件下で、標的細胞とコミュニケーションする、請求項10に記載の幹細胞の単離された集団。
- カプセル化幹細胞の前記単離された集団が、前記外因性DNA配列または前記siRNA、miRNA、もしくはdsRNA配列を微小胞、エキソソームまたは細胞突起により送達する、請求項11に記載の幹細胞の単離された集団。
- 前記siRNA、miRNA、またはdsRNAがウイルス感染を媒介する遺伝子にて特異的である、請求項12に記載の幹細胞の単離された集団。
- エボラウイルス(Ebola virus)に起因する、請求項13に記載のウイルス感染。
- 前記siRNA、miRNA、またはdsRNAが前記NPC1受容体遺伝子にて特異的である、請求項13に記載の幹細胞の単離された集団。
- 間葉系幹細胞の増殖されたクローン集団である、請求項13に記載の幹細胞の単離された集団。
- 動物またはヒト被験者における疾患またはその症状を軽減するため、請求項1に記載の幹細胞の単離された集団をアルギン酸微小環境内に固定化する一方、分子コミュニケーションを持続させることができる、アルギン酸マイクロカプセルを含むマイクロカプセル化システム。
- 前記アルギン酸ポリマーが約1.0%(w/v)〜約3%(w/v)の範囲内の濃度を有する、請求項17に記載のマイクロカプセル化システム。
- 前記アルギン酸ポリマーが約2.5%(w/v)の濃度を有する、請求項18に記載のマイクロカプセル化システム。
- 前記マイクロカプセルが、ポリ−L−リジンのさらなる連続的な外表面コーティングを含む、請求項17に記載のマイクロカプセル化システム。
- 前記マイクロカプセルが、アルギン酸ポリマーをマイクロカプセルに架橋するため、カルシウムまたはバリウムまたはカルシウムとバリウムとの混合物の群からの2価陽イオンを含む、請求項17に記載のマイクロカプセル化システム。
- 前記2価陽イオンが、50〜100mMのカルシウムと2〜50mMのバリウム、好ましくは50mMのカルシウムと50mMのバリウムとの混合物である、請求項17に記載のマイクロカプセル化システム。
- 前記マイクロカプセルが、免疫グロブリンG(IgG)ではなくアルブミンに対して極めて透過性が高い、請求項22に記載のマイクロカプセル化システム。
- 疾患を治療する方法であって、疾患を軽減するため、疾患を患う被験者に請求項17に記載のマイクロカプセル化システム中に固定化された幹細胞を有効量で投与し、前記被験者における免疫応答を調節するステップを含む、方法。
- 被験者に投与された幹細胞の前記用量が前記被験者の1000万個の細胞/kg体重より少ない、請求項24に記載の方法。
- 被験者に投与された幹細胞の前記用量が前記被験者の約600万個の細胞/kg体重である、請求項24に記載の方法。
- マイクロカプセル化システム中に固定化された幹細胞が、静脈内注射、腹腔内注射、リンパ節注射、胸腺注射、脾臓注射、皮下注射またはその組み合わせにより被験者に有効量で投与される、請求項24に記載の方法。
- 幹細胞が、疾患または状態に対する治療を必要とする被験者の診断から1日以内に有効量で投与される、請求項27に記載の方法。
- 幹細胞が治療を必要とする被験者の診断から1日以内に有効量で投与され、続いて幹細胞が2〜7日後に第2の有効量で投与される、請求項28に記載の方法。
- 前記幹細胞が、疾患に対する治療を必要とする前記被験者以外の非自家の被験者に由来する、請求項24に記載の方法。
- 血液または末梢組織における細菌のレベルの増加を伴う疾患を有する被験者における細菌のマクロファージ食作用を増強するため、幹細胞が有効量で投与される、請求項24に記載の方法。
- 前記疾患が敗血症、重度敗血症、または敗血症ショックである、請求項24に記載の方法。
- 疾患を有する被験者の血液中または腹膜内の細菌のレベルを少なくとも100倍減少させるため、幹細胞が有効量で投与される、請求項27に記載の方法。
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WO2021225214A1 (ko) * | 2020-05-04 | 2021-11-11 | 주식회사 티에스셀바이오 | 태반 유래의 세포외 소포의 항염증 항바이러스 효과 조성물 |
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