JP6726726B2 - 組織再生のためのエキソソームおよびマイクロリボ核酸 - Google Patents
組織再生のためのエキソソームおよびマイクロリボ核酸 Download PDFInfo
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Description
概して、1以上の比較的一般的な治療法の使用は、疾患の進行を止めるための試みにおける、損傷または罹患した組織の治療、すでに起きた損傷の逆行、さらなる損傷の予防および患者の健康状態の全体としての改善のために使用される。例えば、多数の病態は、総合的な方法論またはライフスタイルの変更(例えば、心血管疾患、糖尿病などのリスクを減少させるための食事の改善)により容易に治療可能である。多くの場合、より重度の病態は、より進んだ医療的介入を必要とする。薬剤療法または薬学的療法は、特定の疾患を患う患者を治療するために、日常的に施される。例えば、高血圧を患う患者は、血管の圧力および血液量を低下させ、それによって高血圧を治療するために、アンギオテンシン変換酵素(ACE)阻害剤の処方が可能である。さらに、癌患者は、多くの場合、癌性腫瘍の広がりを制限する、および/または癌性腫瘍を根絶するための試みにおいて、さまざまな抗癌化合物のパネルを処方される。外科的方法もまた、特定の疾患または傷害を治療するために用いることができる。場合により、埋め込み装置が、薬学的または外科的療法に加えて、またはそれらの代わりに使用される(例えば、心臓ペースメーカー)。近年では、追加の療法タイプ、例えば、遺伝子療法、タンパク質療法および細胞療法などが、非常に前途有望になってきている。
核酸はヌクレアーゼにより急速に分解されるので、核酸は、一般的に体内では遊離の核酸としては存在しない。ある型の核酸は、膜結合粒子を伴う。このような膜結合粒子は、大部分の細胞型から脱落し、細胞膜の断片から成り、DNA、RNA、mRNA、マイクロRNAおよびタンパク質を含有する。これらの粒子は多くの場合、それらが脱落された細胞の組成を反映する。エキソソームはこのような膜結合粒子の1つのタイプであり、通常、直径約15nmから約95nmの直径範囲であり、この直径範囲は、約15nmから約20nm、20nmから約30nm、約30nmから約40nm、約40nmから約50nm、約50nmから約60nm、約60nmから約70nm、約70nmから約80nm、約80nmから約90nm、約90nmから約95nmおよびこれらの重複範囲を含む。いくつかの実施形態において、エキソソームはより大きい(例えば、約140から約210nmの範囲であり、この範囲は、約140nmから約150nm、150nmから約160nm、160nmから約170nm、170nmから約180nm、180nmから約190nm、190nmから約200nm、200nmから約210nmおよびこれらの重複範囲を含む)。一部の実施形態において、もともとの細胞体から生み出されるエキソソームは、少なくとも1つの次元(例えば直径)において、元々の細胞体の100、200、300、400、500、600、700、800、900、1000、2000、5000、10,000分の1である。
本明細書において、細胞または組織が傷害、損傷、疾患あるいは機能および/または生存能力の喪失につながるいくつかの他の事象を受けた後で、細胞または組織の修復または再生に使用するための方法および組成物を提供する。組織の損傷が存在するかどうかに関わらず、損傷の予防および/または細胞間の核酸(またはタンパク質)の往復のための方法および組成物もまた提供する。
投与のためのより低いプロファイルの送達装置(例えば、より小さいサイズのカテーテルおよび/または針)を可能にするので、エキソソームは、投与にとって特に有益である。いくつかの実施形態において、より小さいサイズのエキソソームは、脈管構造のより小さい、および/またはより回旋した部分を通るそれらの移行を可能にし、順にエキソソームは、最も標的とする組織のより大きな部分に送達され得る。
ク質内容物は、標的組織の修復または再生の少なくとも一部を担っている。例えば、エキソソームにより送達されるタンパク質は、標的組織中の損傷、切断、突然変異またはそうでなければ不適切に機能性もしくは非機能性のタンパク質に取って代わって機能することができる。一部の実施形態において、エキソソームにより送達されるタンパク質は、組織の修復または再生をもたらすシグナル伝達カスケードを開始する。いくつかの実施形態において、エキソソームによるmiRNAの送達は、損傷組織の修復および/または再生の全部または一部を担っている。上記のように、miRNAの送達は、特定のメッセンジャーRNA(例えば、プログラムされた細胞死に関与するメッセンジャーRNA)の翻訳を抑制するように動作することができ、またはメッセンジャーRNAの切断をもたらし得る。いずれの場合も、および一部の実施形態において、組み合わせて、これらの効果は、標的組織において細胞シグナル伝達経路を改変し、本明細書において開示のデータにより実証されるように、細胞の生存能力の改善、細胞複製の増加、有益な解剖学上の効果および/または細胞機能の改善をもたらすことができ、これらはそれぞれ、順に、損傷または罹患した組織の修復、再生および/または機能改善に全体として寄与する。
本明細書に開示の方法および組成物は、広範囲のタイプの損傷または疾患により影響を受けた細胞または組織の修復または再生に使用できる。本明細書に開示の組成物および方法は、遺伝による疾患、細胞または身体の機能障害の治療、正常もしくは異常な細胞の老化との戦い、耐性の誘導、免疫機能の調節に使用できる。さらに、細胞または組織は、外傷、例えば、鈍的衝撃、裂傷、血流の喪失などにより損傷され得る。細胞または組織は、副次的効果、例えば傷害後の炎症、感染症、(例えば、傷害または外傷の結果として遊離したプロテアーゼによる)自己消化によりさらに損傷され得る。本明細書に開示の方法および組成物はまた、ある実施形態において、急性事象の治療にも使用でき、該急性事象は、限定するものではないが、心筋梗塞、脊髄傷害、脳卒中および外傷性脳傷害を含む。いくつかの実施形態において、本明細書に開示の方法および組成物は、慢性疾患の治療に使用でき、該慢性疾患は、限定するものではないが、神経学的障害または神経変性障害(例えば、多発性硬化症、筋委縮性側索硬化症、熱中症、てんかん、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、ドーパミン作動系障害(dopaminergic impairment)、AIDSなどの他の原因によりもたらされる痴呆、局所脳虚血を含む脳虚血、身体外傷、例えば、脳、脊髄、神経または網膜の挫滅または圧迫傷害を含む、CNSにおける挫滅または圧迫傷害、ならびに神経変性を生み出す任意の他の急性の傷害または損傷)、免疫不全、(例えば、骨髄の除去または移植の後の)骨髄の再増殖の促進、関節炎、自己免疫障害、炎症性腸疾患、癌、糖尿病、筋力低下(例えば、筋ジストロフィー、筋委縮性側索硬化症など)、進行性失明(例えば、黄斑変性)および進行性聴力喪失を含む。
一部の実施形態において、エキソソームは、細菌起源の感染症を有する組織を治療するために使用される(例えば、感染性細菌は、ボルデテラ(Bordetella)、ボレリア(Borrelia)、ブルセラ(Brucella)、カンピロバクター(Campylobacter)、クラミジア(Chlamydia)およびクラミドフィラ(Chlamydophila)、クロストリジウム(Clostridium)、コリネバクテリウム(Corynebacterium)、エンテロコッカス(Enterococcus)、エシェリヒア(Escherichia)、フランシセラ(Francisella)、ヘモフィルス(Haemophilus)、ヘリコバクター(Helicobacter)、レジオネラ(Legionella)、レプトスピラ(Leptospira)、リステリア(Listeria)、マイコバクテリウム(Mycobacterium)、マイコプラズマ(Mycoplasma)、ナイセリア(Neisseria)、シュードモナス(Pseudomonas)、リッケチア(Rickettsia)、サルモネラ(Salmonella)、シゲラ(Shigella)、スタフィロコッカス(Staphylococcus)、ストレプトコッカス(Streptococcus)、トレポネーマ(Treponema)、ビブリオ(Vibrio)およびエルシニア(Yersinia)、ならびにこれらの突然変異または組み合わせからなる属の群から選択される)。いくつかの実施形態において、エキソソームは、1以上の細菌機能を阻害または予防し、それによって、感染症の重症度および/または期間を減少させる。いくつかの実施形態において、エキソソームの投与は、細菌(または他の病原体)を補助療法(例えば抗生物質)に感作させる。
いくつかの実施形態において、損傷または疾患により有害な影響を受けた組織の修復または再生に使用するための、エキソソームを含む組成物を提供する。いくつかの実施形態において、組成物は、エキソソームを含む、それからなる、または本質的にそれからなる。いくつかの実施形態において、エキソソームは、核酸、タンパク質またはこれらの組み合わせを含む。いくつかの実施形態において、エキソソーム内の核酸は、(ある実施形態はDNAを含むエキソソームを伴ったが)RNAの1以上の型を含む。RNAは、いくつかの実施形態において、メッセンジャーRNA、snRNA、saRNA、miRNAおよびこれらの組み合わせの1以上を含む。いくつかの実施形態において、miRNAは、miR−26a、miR27−a、let−7e、mir−19b、miR−125b、mir−27b、let−7a、miR−19a、let−7c、miR−140−3p、miR−125a−5p、miR−150、miR−155、mir−210、let−7b、miR−24、miR−423−5p、miR−22、let−7f、miR−146aおよびこれらの組み合わせの1以上を含む。いくつかの実施形態において、組成物は、合成マイクロRNAおよび薬学的に許容されるキャリアを含む、それからなる、または本質的にそれからなる。いくつかのこのような実施形態において、合成マイクロRNAはmiR146aを含む。いくつかの実施形態において、miRNAはpre−miRNA(例えば、成熟していない)であるが、一方で、一部の実施形態において、miRNAは成熟しており、さらに追加の実施形態において、pre−miRNAと成熟miRNAの組み合わせが使用される。
心臓組織の修復および再生のエリアの先行する研究は、心臓組織の修復および/または再生が直接および間接的因子の結果であることを実証していた。例えば、CDCが、再生された心臓組織のおよそ10%を占めていることが示されている。このような研究は、別の機序、例えば、間接的効果が働いていることを示唆している。上記のように、エキソソームおよびそれらの核酸内容物は、間接的機序による細胞または組織の修復および/または再生の提供に、少なくとも一部関与していると思われる。本実施例は、エキソソームおよびそれらの核酸内容物を特徴付けるために設計した。
in vitro実験に着手し、エキソソームの他の細胞型に対する再生促進および抗アポトーシス効果を評価した。エキソソームを、上記のようにCDCまたはNHDF細胞から単離した。エキソソームペレット分画の一部を、その後、培養した新生ラットの心室筋細胞(neonatal rat ventricular myocytes)(NRVM)と一緒に、チャンバースライドにおいておよそ7日間同時インキュベーションした。7日の終わりに、同時培養液を、増殖または細胞死(アポトーシスのマーカーにより測定)の指数変化に関して免疫組織化学により評価した。このプロトコルの概略図を図4に示す。図5Aは、TUNEL染色により測定した、NRVM細胞の死に関するデータを示す。NRVM細胞と、CDCから単離されたエキソソームとのインキュベーションは、対照細胞およびNHDF細胞由来のエキソソームと共にインキュベートされた細胞の両方と比較して、有意に低いアポトーシスの程度をもたらした(CDC:25.2±0.04%;NHDF:45.1±0.05%、p<0.01);対照:41.4±0.05%、n=4、p<0.05)。図5Bは、NRVM細胞とCDCから単離されたエキソソームとのインキュベーションが、対照細胞およびNHDF細胞由来のエキソソームと共にインキュベートされた細胞の両方と比較して、有意により多い細胞増殖活性(Ki67により測定して)をもたらしたことを示している(CDC:42.7±0.04%;NHDF22.5±0.04%;対照:9.1%±0.03%、n=4、p<0.001)。図5Cは、エキソソームなし、NHDF細胞由来のエキソソームと一緒、またはCDC由来のエキソソームと一緒にインキュベートしたNRCMにおけるTUNEL染色の共焦点蛍光顕微鏡分析を示す。図5Aのように、NRCMとエキソソームとのインキュベーションはアポトーシスを減少させ(TUNEL陽性染色が少ない)、CDC由来エキソソームは、NHDF由来のエキソソームよりもより有意な減少を提供した。図5Dは、Ki67染色の共焦点蛍光顕微鏡分析を示す。再度、図5Bに示すデータを総括すると、CDC由来エキソソームは、NRCMの増殖活性の増加をもたらす。まとめると、これらのデータは、細胞死を減少させ、増殖活性を増加させるそれらの能力に基づき、他の細胞型と比較して、CDCが組織の修復および/または再生に関連し特に有益であり得るエキソソームを提供することを示唆している。これらの効果は、いくつかの実施形態において、急性的に損傷された細胞または組織、または、たとえ慢性的に損傷または罹患した細胞または組織において実現された場合でも、損傷した細胞または組織の修復または再生を助ける。
損傷または罹患した領域における細胞または組織の増殖の増加および/または死の減少に加えて、血流の再建または維持は、細胞または組織の修復または再生において中枢的な役割を果たし得る。したがって、血管新生を促進するエキソソームの能力を評価した。ヒト臍帯静脈内皮細胞(HUVEC)を、さまざまな同時インキュベーション条件に供した。これらの条件を図6に表す。簡潔に言うと、HUVEC細胞を培養皿において成長因子低下MATRIGELで成長させた。細胞を、新生ラット心筋細胞培地(NRCM)、CDC由来エキソソーム添加MRCM、NHDF由来エキソソーム添加MRCM、血管細胞基礎培地(VCBM)または血管細胞成長培地、(VCGM)のいずれかにおいて成長させた。図7に示すように、VCGMは、VCBMと比較して強固な血管形成を誘導した(CDC:9393±689;NHDF:2813±494.5、対照、1097±116.1、n=3、p<0.05)。NRCM由来培地は、VCBMと同様の血管形成をもたらした(データ非掲載)。示したように、CDCに由来するエキソソームを添加した培地もまた、有意な血管形成を誘導したが、一方、NHDFに由来するエキソソームを添加した培地は、血管形成が少ないことが示された。さまざまな処理条件からもたらされた血管形成の代表的顕微鏡写真を図8A−8Eに示す。これらのデータは、細胞の増殖および細胞死の減少に対するプラスの効果に加えて、特定の細胞型に由来するエキソソームが血管形成を促進する能力を有することを実証し、この能力は、in vivoで新しい血管系を形成する能力の代表である。したがって、いくつかの実施形態において、エキソソーム(またはエキソソームの内容物、例えばmRNAまたはタンパク質)の、損傷または罹患した組織の領域への投与は、血管新生の増加をもたらす。これが順に、標的領域において細胞および組織の生存能力および/または機能を改善する能力を有する。
上記のin vitro実験結果を考慮して、in vivo実験を実施して、心筋梗塞後の心臓組織再生に対するエキソソーム投与の効果を決定した。急性心筋梗塞(MI)を、左冠動脈前下行枝中部の結紮によりおよそ3ヶ月齢のSCID/Beigeマウスに作り出し、エキソソーム調製物またはビヒクルを、2カ所の梗塞周囲部位に直接可視化の下で注入した。本明細書に開示のように、他の送達経路(例えば、冠動脈内、心筋内、IVなど)が、一部の実施形態において使用される。動物に、対照溶液(イスコフ改変ダルベッコ培地;IMDM)、間葉系幹細胞(MSC−XO)から単離されたエキソソーム、NHDF(NHDF−XO)から単離されたエキソソームまたはCDC(CDC−XO)から単離されたエキソソームのいずれかを与えた。注入後、各実験群の生存率を、時間と共に追跡した。加えて、MRI画像を、梗塞後1日、梗塞後14日および梗塞後30日に収集し、心臓組織の寸法を特徴付けた。図9は、生存実験の結果を要約する。顕著なことには、8匹のCDCエキソソーム注入マウスのうち7匹が30日間生存したことである。対照的に、10匹のNHDFエキソソーム注入マウスはわずか6匹しか30日間生存しなかった。7匹の対照マウスのうち6匹が30日間生存した。MSC−XOデータは非掲載である。全体の生存の改善に加えて、CDCから単離されたエキソソームの投与は、機能の改善をもたらした。これらのデータを図10に表し、これは、CDCに由来するエキソソームにより処置された群において、心筋梗塞後2週間および4週間の両方において有意に改善された左室駆出率(LVEF)を示す。CDCに由来するエキソソームによる処置の結果としてのLVEFの改善は、NHDFエキソソーム群(これは、対照またはMSC−XOにより処置された細胞と差がなかった)に見られる心機能の低下を考慮すると驚くべきである。2週間において、CDCエキソソーム群のLVEFは40.8±2.33%であった(NHDF群32.34±2.0%、MSC−XO群32.41±1.9%およ
び対照群31.31±3.2%と比較;いずれもn=6、p<0.05)。4週間において、CDCエキソソーム群のLVEFは44.03±1.5%であった(NHDF群31.8±1.7%、MSC−XO群31.17±1.5%および対照群31.5±2.7%と比較;いずれもn=6、p<0.05)。
エキソソームが、罹患または損傷した組織の修復および/または再生を容易にできることを理解することだけが重要ではなく、エキソソームの効率的な収集のための工程を理解することもまた重要である。エキソソーム分泌に関与する機序を理解することおよびいくつかの実施形態が、エキソソーム単離の効率の最適化を可能にする。
上記のように、一部の実施形態において、エキソソーム由来産物(例えば、核酸もしくはタンパク質またはこれらの組み合わせ)は、損傷または罹患した細胞または組織に再生効果を提供するために投与することができる。ある実施形態において、DNAがエキソソームから単離できるが、一部の実施形態において、RNAがエキソソームから単離できる(DNAに加えて、またはその代わりに)。特定の型のRNA、例えばマイクロRNA(miRNAまたはmiR)などが、エキソソームにより担持されることが公知である。上記のように、miRNAは、多くの場合標的メッセンジャーRNA転写産物(mRNA)に対する相補配列に結合し、それによって、翻訳抑制、標的mRNAの変性および/または遺伝子サイレンシングをもたらすことによって、転写後レギュレーターとして機能する。エキソソームに含有されるmiRNAについてより理解を深めるために、miRNAのプロファイリング実験を実施した。エキソソームをCDCおよびNHDFの両方から上記のように調製し、全RNAを、確立された方法によってエキソソームから単離した。cDNAを全RNAから作製し、RT PCR反応において鋳型として使用して、miRNAのパネルの発現レベルを決定した。図18Aは、NHDF細胞と比較した、CDC中のさまざまなmiRNAの発現レベルを表す(データは、NHDF発現に関する倍数変化として表し、NHDF発現がX軸における「0」値である)。図のように、CDCおよび対照細胞の間で差次的発現を示すさまざまなmiRNAが存在する。一部の実施形態において、対照細胞を上回る発現の増加を示すmiRNAが、(例えば、このようなmiRNAを含有するエキソソームの投与、またはmiRNAの直接投与により)その後の組織再生に使用される候補である。特に、miR146aは、CDCにおいて250倍を超える発現増加を示す。図18Bは、CDCと比較してNHDF細胞において同等に発現するmiRNA(この実施形態において、同等は、発現の10倍未満の変化に設定した)、CDCにおいて有意に上方制御されるmiRNA(右)およびCDCにおいて有意に下方制御されるmiRNA(左)の一覧表を示す。しかし、一部の実施形態において、被験細胞型に依存して、他のmiRNAが発現の改変を示す。例えば、一部の実施形態において、対照細胞と比較して、発現の低下を示すmiRNAは、組織再生におけるその後の使用の候補である。miRNA発現が上方制御されるか、または下方制御されるかが、miRNAが、その後翻訳の抑制または翻訳のディスク阻止に関連する経路に関与するかどうかに関係し得る。
Claims (9)
- 心筋球由来細胞(CDC)から回収された複数のエキソソームを含み、
前記エキソソームがmiR−146a及びmiR−210を含む、医薬組成物。 - 前記エキソソームが、miR27−a、let−7e、miR−19b、miR−125b、miR−27b、let−7a、miR−19a、let−7c、miR−140−3p、miR−125a−5p、miR−150、miR−155、let−7b、miR−24、miR−423−5p、miR−22、let−7f、miR−376c、miR−320a、miR−130a、miR−9、miR−128、miR−143、miR−21、miR−185、miR−23a、およびこれらの組み合わせからなる群から選択される1以上のマイクロRNA断片を更に含む、請求項1に記載の医薬組成物。
- 前記エキソソームが、miR27−a、let−7e、miR−19b、miR−125b、miR−27b、let−7a、miR−19a、let−7c、miR−140−3p、miR−125a−5p、miR−150、miR−155、let−7b、miR−24、miR−423−5p、miR−22、let−7f、およびこれらの組み合わせからなる群から選択される1以上のマイクロRNA断片を更に含む、請求項1に記載の医薬組成物。
- 前記エキソソームが遠心分離により得られる、請求項1から3のいずれか一項に記載の医薬組成物。
- 前記エキソソームが、サイズ排除ろ過により得られる、請求項1から3のいずれか一項に記載の医薬組成物。
- 前記エキソソームが直径約20nmから約90nmである、請求項1から4のいずれか一項に記載の医薬組成物。
- 心筋球または心筋球由来細胞(CDC)の集団をさらに含む、請求項1から6のいずれか一項に記載の医薬組成物。
- 前記心筋球または心筋球由来細胞(CDC)が、前記個体に対して自己由来である、請求項1から7のいずれか一項に記載の医薬組成物。
- 前記心筋球または心筋球由来細胞(CDC)が、前記個体に対して同種異系である、請求項1から7のいずれか一項に記載の医薬組成物。
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