JP2022180432A - 硝子体小胞中の核酸、タンパク質及び小分子の送達方法 - Google Patents
硝子体小胞中の核酸、タンパク質及び小分子の送達方法 Download PDFInfo
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Abstract
Description
本発明は、眼疾患の治療のために治療剤を眼組織に送達するための方法及び組成物に関する。
眼内構造体への核酸(例えば、遺伝子、mRNA、DNA、siRNA、miRNAまたは他の非コードRNA)、タンパク質及び/または小分子の送達を伴う療法は、眼疾患を含めた疾患において極めて大きな治療的可能性を有する。しかしながら、生物学的活性分子をその標的部位に直接送達することができないことは、眼疾患の治療における大きな制約である。血液-網膜関門は網膜内へのほとんどの分子の透過を防止する。同様の制約が他の眼組織に存在する。
[本発明1001]
1つ以上の房水細胞外小胞及び/または硝子体液細胞外小胞
を含む組成物であって、
前記細胞外小胞が、1つ以上の外因性作用物質を含有するように改変されている、
前記組成物。
[本発明1002]
前記1つ以上の外因性作用物質が、核酸分子、タンパク質またはポリペプチド、小分子、ホルモン及びそれらの任意の組み合わせからなる群から選択される、本発明1001の組成物。
[本発明1003]
前記外因性作用物質が、リボ核酸、低分子RNA分子、相補的RNA、非コードRNA分子、siRNA、pi-RNA分子、マイクロRNA分子、sno-RNA分子、長鎖非コードRNA分子、伝令RNA分子、リボソームRNA分子、アンチセンス核酸分子、ロックド核酸(LNA)、アンタゴミル、CRISPR/Cas遺伝子編集RNA、トランス活性化型crRNA(tracrRNA)、「足場」配列からなる短鎖合成RNA(gRNA)、低分子カハール体特異的RNA(scaRNA)、天然シスアンチセンスsiRNA(cis-nat-siRNA)、トランス作用性siRNA(tasiRNA)、反復配列関連低分子干渉RNA(rasiRNA)、7SK、転移-伝令RNA(tmRNA)、転移RNA(tRNA)、7SL RNA、シグナル認識粒子RNA(SRP)及びそれらの任意の組み合わせからなる群から選択される核酸分子を含む、本発明1002の組成物。
[本発明1004]
前記外因性作用物質が、低分子デオキシリボ核酸(DNA)分子、cDNA分子、オリゴヌクレオチド、ロックド核酸(LNA)、デオキシリボ核酸アプタマー、デオキシリボ核酸ザイム及びそれらの任意の組み合わせを含む、本発明1002の組成物。
[本発明1005]
前記外因性作用物質が、
ウイルスベクター、細菌ベクター、プラスミドベクターまたはそれらの任意の組み合わせの中に入った状態で運ばれる、本発明1001~1004のいずれかの組成物。
[本発明1006]
前記外因性作用物質がタンパク質またはポリペプチドを含む、本発明1001の組成物。
[本発明1007]
前記外因性作用物質が小分子を含む、本発明1001の組成物。
[本発明1008]
前記1つ以上の細胞外小胞が、哺乳動物対象の房水及び/または硝子体液を含有する眼内液から単離される、本発明1001の組成物。
[本発明1009]
前記哺乳動物対象がヒト対象またはウシ対象である、本発明1008の組成物。
[本発明1010]
前記1つ以上の細胞外小胞が、真核細胞特異的な標的指向性分子を前記小胞の外表面に提示するようにさらに改変されている、本発明1001の組成物。
[本発明1011]
前記外因性作用物質が治療剤を含み、
前記組成物が、薬学的に許容できる担体をさらに含んでいる、
本発明1001の組成物。
[本発明1012]
徐放性または持続放出性材料へと製剤化される、本発明1001の組成物。
[本発明1013]
対象の選定された細胞または組織に治療剤を送達する方法であって、以下の段階:
本発明1001~1012のいずれかの組成物を提供する段階であって、前記外因性作用物質が治療剤を含む、段階;ならびに、
治療剤を含有するように改変された前記房水細胞外小胞及び/または硝子体液細胞外小胞を前記対象の前記選定された細胞または組織に送達するのに有効な条件下で、前記対象に前記組成物を投与する段階
を含む、前記方法。
[本発明1014]
眼疾患を有する対象を選択する段階をさらに含み、
前記投与する段階が、前記眼疾患の治療として前記治療剤を前記対象の眼細胞または組織に送達するために行われる、
本発明1013の方法。
[本発明1015]
前記投与が、局所投与、全身投与、眼周囲投与または眼内投与から選択される、本発明1014の方法。
[本発明1016]
前記眼内投与が、前房内(intracameral)投与、硝子体内投与または網膜下投与によって行われる、本発明1015の方法。
[本発明1017]
前記眼周囲投与が、結膜下注射、テノン嚢下注射、直接眼周囲注射または眼周囲蓄積注射によって行われる、本発明1015の方法。
[本発明1018]
前記全身投与が、静脈内投与、経口投与、動脈内投与、吸入、鼻腔内投与、腹膜腔内投与、腹腔内投与、皮下投与、関節内投与、クモ膜下腔内投与、経硬膜投与、経皮(transdermal)投与、粘膜下投与、舌下投与、経腸投与、非経口投与、経皮(percutaneous)投与、関節周囲投与または脳室内投与によって行われる、本発明1015の方法。
[本発明1019]
硝子体液及び/または房水を含む哺乳動物眼内液試料を提供する段階;
前記眼内液試料から細胞外小胞を単離する段階;ならびに
前記単離された細胞外小胞の中に前記1つ以上の外因性作用物質を挿入する段階
を含む、本発明1001の組成物を作る方法。
[本発明1020]
前記挿入する段階が、電気穿孔、トランスフェクション、ウイルスベクター送達またはそれらの任意の組み合わせを用いて行われる、本発明1019の方法。
[本発明1021]
前記挿入する段階に先立って、前記単離された細胞外小胞の内在性内容物を除去する段階
をさらに含む、本発明1019の方法。
[本発明1022]
前記除去する段階が、紫外線照射を用いて行われる、本発明1021の方法。
本発明は、健常なヒト及びウシの眼の硝子体液及び房水の小胞ネットワークの予想外な発見に基づく。このネットワークの小胞には、それによって他の眼組織へ短距離及び長距離輸送される多様なタンパク質ならびにコード及び非コードRNAの積荷が装填されている。本明細書において記載及び実証されるように、これらの小胞は、健常個体の眼内液から安全に単離されること、及び改変されて治療薬送達ビヒクルとしての役割を果たすことができる。
死後試料からの組織の調製及び処理。疾患を有さない死後ヒトの眼を得た(The Eye-Bank for Sight Restoration,New York,NY)。ウシの眼は地域の精肉店(Green Village Packing,Green Village,New Jersey)から入手した。解剖手順のために眼を氷上の100mmのプラスチック製ペトリ皿に入れてRNA及びタンパク質の変性を防止した。SZX-16実体解剖顕微鏡(Olympus)を使用して、眼球に付着した眼窩脂肪及び眼外筋肉を取り除いた。50mMのTris-HCl、150mMのNaClを含有しpHが8.0に調節された氷冷Tris緩衝生理食塩水(TBS)5mlで眼球を4℃で1分間すすいだ。16g針を使用して(それぞれヒト及びウシの眼の)縁から4mmまたは8mm後ろのところで強膜切開し、次いでハサミで周囲を矢状に切開することによって硝子体を切断して眼球を前方カップと後方カップとに分けた。有形硝子体を切って取り出すため及び硝子体と眼構造体との接着を断ち切るためにハサミを使用した。脈絡膜メラノサイト及び神経網膜が硝子体へ混入することを回避するように気を付けた。その他の、脈絡膜、網膜、毛様体、水晶体及び角膜を含めた眼組織を特定して切り離した。組織試料はTBS(pH8.0)によって4℃で1分間すすいだ。電子顕微鏡観察及びEV単離のために、採集した標本を固定せずにすぐさま以下に記載するように処理した。免疫組織化学、ウェスタンブロッティングまたはEDC-ホルマリン固定のために使用する試料は15mlの遠心分離チューブに入れ、TBS(pH8.0)で希釈された4%のホルマリン(ホルムアルデヒド、パラホルムアルデヒドまたはPFAとしても知られる)10mlに4℃で少なくとも24時間浸した。「ホルマリン単独」の組織を4℃で5分間、TBS(pH8.0)で3回洗浄し、それ以上は処理またはEDCによる固定を行わなかった。ホルマリン単独の組織を免疫組織化学、ウェスタンブロッティングまたは、核酸及びタンパク質撮像のために使用した。EDC-ホルマリン固定標本は以下に記載するようにさらに処理した。
本明細書に記載の試験は、EVを細胞外空間に保持すべく組織固定を最適化することに重点的に取り組んだ。組織の組織学的及び形態学的構造を保存するために、従来の固定方法は、10%ホルマリンを採用してタンパク質-タンパク質架橋を作り出す。固定プロセスは一般的に室温以上での処理ステップまたはインキュベーションを伴うが、高い温度は、ホルマリンのタンパク質-タンパク質架橋(Shi et al.,“Antigen Retrieval in Formalin-fixed,Paraffin-embedded Tissues:An Enhancement Method for Immunohistochemical Staining Based on Microwave Oven Heating of Tissue Sections,”J Histochem Cytochem 39:741-748(1991)、Ikeda et al.,“Extraction and Analysis of Diagnostically Useful Proteins From Formalin-fixed,Paraffin-embedded Tissue Sections,”J Histochem Cytochem 46:397-403(1998)。参照によりその全体が本明細書に援用される)及びRNA-タンパク質架橋(Pena et al.,“miRNA In Situ Hybridization in Formaldehyde and EDC-fixed Tissues,”Nat Methods 6:139-141(2009)。参照によりその全体が本明細書に援用される)を逆戻りさせることが知られている。図1Aの模式図に示すようにナノメートルサイズのEVは室温以上での洗浄ステップの間にホルマリン固定組織標本から逸出するという仮説を立てた。ホルマリン固定組織からのEV逸出の程度を調べるために、ホルマリン固定ウシ硝子体組織を様々な時点にわたって37℃の洗浄用緩衝液に浸し、その後に上清を回収した。上清の超微細構造内容物を、透過型電子顕微鏡法(TEM)を用いて撮像し、早ければ30分で、相当数のEVが洗浄用緩衝液中に存在しておりホルマリン固定組織から漏出したということが分かった(図1B~図1C)。4℃より高い温度への曝露はRNAの脱出も招き(Pena et al.,“miRNA In Situ Hybridization in Formaldehyde and EDC-fixed Tissues,”Nat Methods 6:139-141(2009)。参照によりその全体が本明細書に援用される)、おそらくタンパク質の脱出も招いた。これらのナノメートルサイズのEVを組織中及び周囲の細胞外空間内に保持するために、EVタンパク質の正に帯電したアミノ基側鎖とカルボキシル基との不可逆的架橋を水溶性カルボジイミドであるEDCによって作り出すさらなる固定ステップを追加した。このようにして、試料をまずホルマリンで固定することと、続いてその後にEDCを架橋することとを伴う2ステップ固定を行った。EDC-ホルマリン固定後に硝子体組織を様々な温度の洗浄用緩衝液中に入れ、上清をTEMで撮像した(図1D)。上清中にEVは検出されなかった(図1E)。EDC-ホルマリン上清中及び洗浄用緩衝液対照中に微粒子状物質が観察された(図1F)。よってEVはEDC-ホルマリン固定組織から脱出しなかった。硝子体組織からのEVの逸出を定量するためにウェスタンブロッティングを用いて既知のエオジンマーカーTSG-101を検出した。ホルマリン固定硝子体の上清は、上清における顕著な量のTSG-101信号を示した(図1G)。これらのデータは、ホルマリン固定組織では相当量のEVが洗浄用緩衝液中に失われることを示唆している。
目的は、正常硝子体組織(図2A)の細胞外空間におけるEVの構造的関係性を可視化することであり、したがって、ウシ硝子体の従来の固定(ホルマリン単独)をEDC-ホルマリンと比較し、次いで原位置でEVを可視化することを試みた。EVはタンパク質を含有することが知られており、それゆえ全載試料において全タンパク質を標識し、その後、多光子顕微鏡法で撮像した(図2B~図2D)。タンパク質を標識するために、アミンと共有結合する細胞透過性蛍光色素であるカルボキシフルオレセインスクシンイミジルエステル(CFSE)(Bronner-Fraser,M.,“Alterations in Neural Crest Migration by a Monoclonal Antibody That Affects Cell Adhesion,”J Cell Biol 101:610-617(1985)。参照によりその全体が本明細書に援用される)を使用した。ホルマリン固定組織は硝子体細胞の近傍または内部で陽性タンパク質信号を示すが細胞外タンパク質信号の証拠は示さないということが分かった(図2A~図2B、n=4)。これらのデータは、EVが、硝子体組織中に存在していないかホルマリン固定硝子体標本の処理中に失われたかのどちらかであることを示唆していた。対照的に、EDC-ホルマリン固定試料は、大きさ及び形状がEVに合致する細胞外マトリックス中のタンパク質の堅牢な信号を示した(図2C~図2D)。さらに、CFSEで染色されたEDC-ホルマリン固定組織は、ホルマリン単独に比べて有意により多くのEV(120倍)を一貫して示した(図2E、p<0.05)。
EVは、細胞外RNAも含有することが知られており(Valadi et al.,“Exosome-mediated Transfer of mRNAs and MicroRNAs is a Novel Mechanism of Genetic Exchange Between Cells,”Nat Cell Biol 9:654-659(2007)。参照によりその全体が本明細書に援用される)、それゆえ硝子体組織中の細胞外RNAを可視化することを試みた。DNAを染色するだけでなく低親和性ながらRNAも染色するものであるヨウ化プロピジウム(PI)でウシ硝子体核酸を標識した(Suzuki et al.,“DNA Staining for Fluorescence and Laser Confocal Microscopy,”J Histochem Cytochem 45:49-53(1997)。参照によりその全体が本明細書に援用される)。EDC-ホルマリン固定組織を共焦点顕微鏡法で撮像することで、細胞外RNA及び細胞外タンパク質について陽性である信号が示されたが、細胞外DNAは検出されなかった(図3A~図3B)。細胞外RNAの信号はEVタンパク質信号と共局在していることが見出され(図3A)、細胞外RNAが小胞内にあることが示唆された。対照的に、ホルマリン単独による固定では細胞外RNA及びタンパク質の信号がより大幅に小さくなった(図3C)。さらに、EDC-ホルマリン固定組織中の硝子体細胞の細胞質中には、従来の固定と比較してより大幅に多いRNAが保持されていることも分かった。細胞外PI信号が確かにRNAであることを検証するためにEDC-ホルマリン固定試料をRNアーゼで処理し、細胞外信号が顕著に減少したことが分かった(図4A~図4B)。標準的な蛍光顕微鏡を使用してEV信号の増強が観察され得るか否かを判定するために、ホルマリン及びEDC-ホルマリンで固定された硝子体試料からの画像をCFSE及びPIで染色し、その後、広視野蛍光顕微鏡でキャプチャし、比較した。データは、EDC-ホルマリン固定試料が細胞外タンパク質及びRNAの強い信号を実証した一方で、ホルマリン固定標本が細胞外タンパク質信号を示さずに終わったことを示している(図5A~図5B)。総合するとこれらのデータは、EVタンパク質及び細胞外RNAを組織中に保持する上で、EDC-ホルマリン固定がホルマリン固定単独よりも優れていることを示唆している。しかもこの技術は、原位置でのEVの硝子体組織内での空間的関係性を決定することを可能にする。
EDC-ホルマリン固定組織からの顕微鏡写真で観察された知見を、EVを可視化するために用いられる他の方法と相関させるために、硝子体EVの超微細構造をTEMで試験した(Raposo et al.,“B Lymphocytes Secrete Antigen-presenting Vesicles,”J Exp Med 183:1161-1172(1996)。参照によりその全体が本明細書に援用される)。ウシ硝子体標本は酢酸ウラニル及びクエン酸塩によって負に染色され、画像は、大きさに多形性がある相当量のEVを示した(図6A)。次に、ウシ硝子体から単離したEVを、タンパク質のアミンと共有結合する高電子密度色素であるCFSEで標識し(Raposo et al.,“B Lymphocytes Secrete Antigen-presenting Vesicles,”J Exp Med 183:1161-1172(1996)。参照によりその全体が本明細書に援用される)、画像は、EVが豊富にあることを濃い小胞内染色によって示した(図6B)。EVはRNAを含有することが知られているので(Valadi et al.,“Exosome-mediated Transfer of mRNAs and MicroRNAs is a Novel Mechanism of Genetic Exchange Between Cells,”Nat Cell Biol 9:654-659(2007)。参照によりその全体が本明細書に援用される)、ウシ硝子体から単離したEVを高電子密度かつ核酸選択的な色素アクリジンオレンジ(AO)による染色の後に撮像し、それはEV内の陽性信号を示した(図6C)。全載ウシ硝子体を別の高電子密度核酸染色剤である臭化エチジウムで染色することによってもEV内の陽性信号が示された(図6D)。ウシ硝子体EVの濃度及び粒度分布を決定するためにナノ粒子軌跡解析(NTA)(Dragovic et al.,“Sizing and Phenotyping of Cellular Vesicles Using Nanoparticle Tracking Analysis,”Nanomedicine 7:780-788(2011)。参照によりその全体が本明細書に援用される)を用い、細胞外小胞の濃度は、ウシの眼1個あたり20億個超のEVに相当する、1mlあたり少なくとも2.98×107個粒子(標準誤差は1mlあたり±8.98x106粒子)であることが分かった(図6E)。データは、細胞外小胞の大きさが不均一であることを示し、平均が212nm(標準誤差±10nm)、最頻値が143nm(標準誤差±20.4nm)、ピークが125nm及び215nmであり、いくつかの細胞外小胞は最大で550nmであった(図6E)。NTAによって測定されたEVの大きさは、多光子顕微鏡法によって観察されたEVの大きさとは異なっていたが、これはおそらく、大きめのEVを除去する超遠心分離に基づく単離方法による結果である(van der Pol et al.,“Recent Developments in the Nomenclature,Presence,Isolation,Detection and Clinical Impact of Extracellular Vesicles,”.J Thromb Haemost 14:48-56(2016)。参照によりその全体が本明細書に援用される)。眼全体における硝子体EVの分布を決定するために、死後ヒトの眼に対してTEMを実施し、硝子体基底部及び毛様体の付近において多数の硝子体EVの濃度が高いことが実証された(図6F~図6G)。死後ヒト硝子体標本から精製されAOで染色されたEVも、EVに合致する大きさ及び形状を明らかにした(図6H~図6I)。これらのデータは、硝子体EVが確かに存在し、その数が豊富であり、大きさが不均一であり、CFSE及び核酸選択的色素によって陽性に染色される、ということを示している。
硝子体EVがEV関連タンパク質を発現するか否かを判定するために、液体クロマトグラフィー質量分析(LC-MS)を用いてプロテオーム解析を行い、(低速遠心分離で細胞が除去された)ウシ硝子体をEV単離画分と比較した(n=6のウシ硝子体。試料をプールした)。硝子体及びEV単離画分は、合同したプロテオーム一覧において合計1686個のタンパク質を示し、682個及び464個のタンパク質がそれぞれ全硝子体画分またはEV画分において濃縮されており、540個のタンパク質はどちらにおいても存在量が同程度であった。EV及び全硝子体画分において検出された1779個のタンパク質の包括的一覧を以下の表3に示す。表3の一覧は、タンパク質をそのタンパク質名(1列目)、ならびにそのUniProtKB受託番号及び名前を含むタンパク質識別子で同定している。表3に列挙される各タンパク質について細胞不含硝子体画分と比較したときのEV画分におけるタンパク質量のlog2差が5列目に列挙されているが、これは、EV濃縮画分(3列目)及び細胞不含硝子体画分(4列目)における無標識定量(LFQ)強度によって定量したタンパク質量に基づくものである。EV画分において濃縮されているタンパク質を「EV画分のみ」と表す(5列目)。タンパク質の合計強度をiBAQ値で表す(6列目)。
*TSG101=腫瘍感受性遺伝子101;†HSP=熱ショックタンパク質
**表1の参考文献(参照によりその全体が本明細書に援用される):
硝子体EVが、RNA及びタンパク質積荷を標的細胞内に移入させることが知られている他のEVと同様の生物学的活性を有するか否かを調査した。初期の研究では、試験管内でEVがmRNA及びマイクロRNAを細胞内へ運ぶことが示された(Valadi et al.,“Exosome-mediated Transfer of mRNAs and MicroRNAs is a Novel Mechanism of Genetic Exchange Between Cells,”Nat Cell Biol 9:654-659(2007)、Skog et al.,“Glioblastoma Microvesicles Transport RNA and Proteins That Promote Tumour Growth and Provide Diagnostic Biomarkers”Nat Cell Biol 10:1470-1476(2008)。参照によりその全体が本明細書に援用される)。それゆえ、ウシ及び死後ヒトの硝子体EVがそれらの内在性RNAを培養細胞内に移入させる能力を試験した。ウシまたはヒト硝子体EV RNAをAO蛍光色素で標識し、EV画分を精製し(図8A~図8B)、網膜色素上皮細胞(ARPE-19)を多量の標識EVに曝露した。ウシEV-RNAの場合、培養ARPE-19細胞において48時間目に最大で96.2%±01.9%のトランスフェクション率が認められ(図9A~図9C)、これは対照よりも有意に高かった。ヒト胚性腎臓細胞も好結果にトランスフェクトされた(図9D~図9F)。単離された死後ヒト硝子体EVも、24時間目に、標識EV-RNAをARPE-19細胞に対照よりも有意に高く96%±3.8%移入させることができた(図9G~図9I)。
生体内で硝子体EVのトランスフェクション効率の妥当性を立証すること及び眼内の標的細胞を判定することを試みた。電気穿孔によって0.5μgのBSA-フルオレセインが装填された希釈量のEV(0.025μg)を、眼内送達のために用いられる一般的技術である硝子体内注射によって齧歯動物の眼に投与した。処置後3日目にEVは、網膜を横切った証拠を示さず、内境界膜を透過しない(図11A)。注射後3週目に、複数の網膜細胞層においてトランスフェクションが認められた(図11B~図11D)。特異性対照については、PBS単独、または電気透過化なしでBSA-フルオレセインと混合したEV試料ではトランスフェクションの証拠が認められなかった。総合するとこれらのデータは、硝子体EVが生物学的に活性であり、生体内で組換えタンパク質を送達するベクターとして機能する、ということを示している。加えて、硝子体EVは網膜細胞を標的とし、持続的トランスフェクションを最大で3週間にわたって維持する。
フルオレセインと結合した組換えウシ血清アルブミン(BSA)(BSA-フルオレセイン)が電気穿孔(300V)によって装填されたウシEVをマウスの眼に注射した。注射後3週目にマウス眼切片をBSA-フルオレセイン送達について調べ、図12Aの顕微鏡写真に示すように角膜において内皮細胞及び角膜細胞からの送達が認められた。電気穿孔なし(0V)でBSA-フルオレセインと混合したウシEVの対照群からの注射3週間後の画像は、内皮細胞においても角膜細胞においても発現を示さないが、角膜上皮の非特異的な染色は示している(図12B)。図12Cは、電気穿孔(300V)によってBSA-フルオレセインが装填されたEVを注射してから3週間後のマウスの眼からの代表的な共焦点蛍光顕微鏡写真であり、毛様体、毛様体無色素上皮細胞における信号を示す。図12Dの画像は、視細胞、内網状層(IPL)、網膜色素上皮(RPE)細胞及び脈絡膜におけるBSA-フルオレセインの堅牢な発現を示す。全組織切片中の核はヘキストブルーで染色され、これらは図12A~図12Dの中央パネルに示されている。融合画像を図12A~図12Dの左端パネルに示す。図12Eの画像は、網膜色素上皮細胞(RPE)及び脈絡膜におけるBSA-フルオレセインの発現を示す。
外因性低分子干渉RNAによる改変を硝子体小胞が可能とするか否かを判定するために、シアニン3と結合した抗GAPDH siRNAを小胞内に電気穿孔を用いて導入した。様々な電気穿孔電圧で小胞内に装填したGAPDH siRNA-Cy3に、ARPE-19細胞を曝露し、siRNA装填小胞は、より高い電圧ではより高い効率で(図13A~図13C)、より低い電圧ではより低い効率で(図13D~図13F)、細胞にトランスフェクトしたが、電気穿孔なしでは検出不可能であった(図13G~図13H)、ということが見出された。図13Iは、トランスフェクション効率を電気穿孔電圧に関して示すグラフである。
次に、眼内液小胞の起源を同定することを試みた。小胞は毛様体から産生されるという仮説を立てた、というのも、1)硝子体液コラーゲン線維の濃度は、水晶体の後方で毛様体と隣接している硝子体基底部の近くにおいて最も高く、2)毛様体は、表面積が大きいこと及び房水を産生することが知られているからである。それゆえ、酢酸ウラニルで染色したウシ毛様体の組織切片に対してTEMを行い、無色素上皮において細胞内空間内へと発生している小胞が見つかった(図14A~図14D)。色素上皮における小胞発生は認められなかった(図14E)。これらのデータは、毛様体が眼内の小胞の少なくとも部分的な供給源であることを示唆している。
上に述べたとおり、ウシ小胞は多様なプロテオームを含有する。これらの小胞は、外因性タンパク質を装填されることができ、タンパク質を標的細胞に送達するツールとして使用されることができると推論した。かくして、硝子体小胞が外因性タンパク質による改変を可能とするか否かを調べた。フルオレセインと結合したウシ血清アルブミン(BSA-フルオレセイン)を様々な電圧で電気穿孔を用いて小胞内に導入し、装填されたBSA-フルオレセイン小胞にARPE-19細胞を曝露した。BSA-フルオレセイン装填小胞は、100Vを用いてタンパク質を装填された場合(図15D~図15F)よりも350Vを用いてタンパク質を装填された場合(図15A~図15C)の方が大幅に高い効率でARPE-19細胞にトランスフェクトしたことが見出された。電気穿孔なしではトランスフェクションは認められなかった(図15G~図15H)。
硝子体小胞が高レベルであることから、小胞は房水中で後眼房内に位置している可能性もあるという仮説を立てるに至った。かくして、房水をTEM撮像法で調べ、広く分布している小胞が見つかった(図16A~図16C)。小胞画分を単離し、ナノ粒子軌跡解析によって小胞の大きさ及び濃度を決定し、これによって、濃度が1mlあたり少なくとも1.10×108個粒子(図16E、標準誤差は1mlあたり±9.25×107個粒子、n=10)、眼球1個あたり1mlあたり合計2.7×108個粒子(図16E、n=10)であり、平均の大きさが155nm(標準誤差±27.9nm)、及び最頻値が88.7nm(標準誤差±34.1nm)であることが示された。興味深いことに、房水中の小胞の粒度分布は硝子体小胞に比べて大幅に小さかった。
要約すると、従来のホルマリン固定に基づく技術は哺乳動物組織からの相当量のEVの脱出を招き、この結果として原位置でのEVの可視化は一貫性がなくなるかまたは陰性になる。それに対して、EDC-ホルマリン固定は組織中でのEVの保持を著しく改善し、原位置での堅牢なEV撮像を可能にする。この方法は、生物学的機能がほとんどないと長い間みなされてきた眼の正常硝子体液において以前に同定されなかったEVのネットワークを明らかにした。加えて、本明細書において提示されるデータは、試験管内及び生体内で組換えタンパク質及び核酸分子を送達するベクターとして硝子体EVを操作することができることを実証する。結論として、この方法は、正常組織標本または、眼疾患、神経障害及びがんなどEVによって媒介されると考えられる多種多様な疾患を含む罹患組織標本において、EVの構造及び機能を研究するための新しい可能性を切り開く。
Claims (22)
- 1つ以上の房水細胞外小胞及び/または硝子体液細胞外小胞
を含む組成物であって、
前記細胞外小胞が、1つ以上の外因性作用物質を含有するように改変されている、
前記組成物。 - 前記1つ以上の外因性作用物質が、核酸分子、タンパク質またはポリペプチド、小分子、ホルモン及びそれらの任意の組み合わせからなる群から選択される、請求項1に記載の組成物。
- 前記外因性作用物質が、リボ核酸、低分子RNA分子、相補的RNA、非コードRNA分子、siRNA、pi-RNA分子、マイクロRNA分子、sno-RNA分子、長鎖非コードRNA分子、伝令RNA分子、リボソームRNA分子、アンチセンス核酸分子、ロックド核酸(LNA)、アンタゴミル、CRISPR/Cas遺伝子編集RNA、トランス活性化型crRNA(tracrRNA)、「足場」配列からなる短鎖合成RNA(gRNA)、低分子カハール体特異的RNA(scaRNA)、天然シスアンチセンスsiRNA(cis-nat-siRNA)、トランス作用性siRNA(tasiRNA)、反復配列関連低分子干渉RNA(rasiRNA)、7SK、転移-伝令RNA(tmRNA)、転移RNA(tRNA)、7SL RNA、シグナル認識粒子RNA(SRP)及びそれらの任意の組み合わせからなる群から選択される核酸分子を含む、請求項2に記載の組成物。
- 前記外因性作用物質が、低分子デオキシリボ核酸(DNA)分子、cDNA分子、オリゴヌクレオチド、ロックド核酸(LNA)、デオキシリボ核酸アプタマー、デオキシリボ核酸ザイム及びそれらの任意の組み合わせを含む、請求項2に記載の組成物。
- 前記外因性作用物質が、
ウイルスベクター、細菌ベクター、プラスミドベクターまたはそれらの任意の組み合わせ
の中に入った状態で運ばれる、請求項1~4のいずれか1項に記載の組成物。 - 前記外因性作用物質がタンパク質またはポリペプチドを含む、請求項1に記載の組成物。
- 前記外因性作用物質が小分子を含む、請求項1に記載の組成物。
- 前記1つ以上の細胞外小胞が、哺乳動物対象の房水及び/または硝子体液を含有する眼内液から単離される、請求項1に記載の組成物。
- 前記哺乳動物対象がヒト対象またはウシ対象である、請求項8に記載の組成物。
- 前記1つ以上の細胞外小胞が、真核細胞特異的な標的指向性分子を前記小胞の外表面に提示するようにさらに改変されている、請求項1に記載の組成物。
- 前記外因性作用物質が治療剤を含み、
前記組成物が、薬学的に許容できる担体をさらに含んでいる、
請求項1に記載の組成物。 - 徐放性または持続放出性材料へと製剤化される、請求項1に記載の組成物。
- 対象の選定された細胞または組織に治療剤を送達する方法であって、以下の段階:
請求項1~12のいずれか1項に記載の組成物を提供する段階であって、前記外因性作用物質が治療剤を含む、段階;ならびに、
治療剤を含有するように改変された前記房水細胞外小胞及び/または硝子体液細胞外小胞を前記対象の前記選定された細胞または組織に送達するのに有効な条件下で、前記対象に前記組成物を投与する段階
を含む、前記方法。 - 眼疾患を有する対象を選択する段階をさらに含み、
前記投与する段階が、前記眼疾患の治療として前記治療剤を前記対象の眼細胞または組織に送達するために行われる、
請求項13に記載の方法。 - 前記投与が、局所投与、全身投与、眼周囲投与または眼内投与から選択される、請求項14に記載の方法。
- 前記眼内投与が、前房内(intracameral)投与、硝子体内投与または網膜下投与によって行われる、請求項15に記載の方法。
- 前記眼周囲投与が、結膜下注射、テノン嚢下注射、直接眼周囲注射または眼周囲蓄積注射によって行われる、請求項15に記載の方法。
- 前記全身投与が、静脈内投与、経口投与、動脈内投与、吸入、鼻腔内投与、腹膜腔内投与、腹腔内投与、皮下投与、関節内投与、クモ膜下腔内投与、経硬膜投与、経皮(transdermal)投与、粘膜下投与、舌下投与、経腸投与、非経口投与、経皮(percutaneous)投与、関節周囲投与または脳室内投与によって行われる、請求項15に記載の方法。
- 硝子体液及び/または房水を含む哺乳動物眼内液試料を提供する段階;
前記眼内液試料から細胞外小胞を単離する段階;ならびに
前記単離された細胞外小胞の中に前記1つ以上の外因性作用物質を挿入する段階
を含む、請求項1に記載の組成物を作る方法。 - 前記挿入する段階が、電気穿孔、トランスフェクション、ウイルスベクター送達またはそれらの任意の組み合わせを用いて行われる、請求項19に記載の方法。
- 前記挿入する段階に先立って、前記単離された細胞外小胞の内在性内容物を除去する段階
をさらに含む、請求項19に記載の方法。 - 前記除去する段階が、紫外線照射を用いて行われる、請求項21に記載の方法。
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