JP6184991B2 - Rna干渉のrna配列特異的メディエータ - Google Patents
Rna干渉のrna配列特異的メディエータ Download PDFInfo
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- JP6184991B2 JP6184991B2 JP2015012724A JP2015012724A JP6184991B2 JP 6184991 B2 JP6184991 B2 JP 6184991B2 JP 2015012724 A JP2015012724 A JP 2015012724A JP 2015012724 A JP2015012724 A JP 2015012724A JP 6184991 B2 JP6184991 B2 JP 6184991B2
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- mrna
- rna
- stranded rna
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- gene
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Description
本出願は、2001年1月31日に出願された米国仮出願第60/265,232号明細書および2000年3月30日に出願された米国仮出願第60/193,594号明細書の利益を主張し、35U.S.C.セクション119 の下で2000年12月1日に出願された欧州特許出願第00 126 325.0の優先権を主張する。上記出願の開示全体が本明細書中に参考として援用される。
本明細書中に記載された研究は、米国国立衛生研究所からの米国公衆衛生局MERIT 助成金(Grant 番号RO1-GM34277 )を通じて米国国立衛生研究所からの助成金によって一部、出資された。米国政府は本発明に所定の権利を有する。
RNA 干渉(interference)または「RNAi」は、二本鎖RNA (dsRNA )がムシに導入された場合、遺伝子発現をブロックすることができるという観察を記載するためにFireおよび共同研究者によって最初に造られた用語である(非特許文献1)。dsRNA は、脊椎動物を含む多くの生物において遺伝子特異的、転写後サイレンシングを行い、遺伝子機能を研究するための新しいツールを提供した。RNAiは、mRNA分解に関与するが、この干渉の根底にある生化学的機序の多くは不明なままである。インビトロでのRNAiの本質的特性の要約が、現象の生化学的解析のために必要である。
〔1〕対応するmRNAのRNA 干渉を媒介する約21〜約23ヌクレオチドの単離されたRNA、
〔2〕末端3’ヒドロキシル基を含有してなる〔1〕記載の単離されたRNA、
〔3〕化学合成されたRNA 、または天然に存在するRNA のアナログである、〔1〕記載の単離されたRNA、
〔4〕1つ以上のヌクレオチドの付加、欠失、置換または変化により〔1〕記載のRNA とは異なるものである、〔1〕記載の単離されたRNA のアナログ、
〔5〕転写サイレンシングにより対応する遺伝子を不活化する約21〜約23ヌクレオチドの単離されたRNA、
〔6〕RNA 干渉を媒介する可溶性抽出物、
〔7〕抽出物がショウジョウバエ胚に由来するものである、〔6〕記載の可溶性抽出物、
〔8〕抽出物が、合胞体胞胚葉ショウジョウバエ胚に由来するものである、〔7〕記載の可溶性抽出物、
〔9〕(a )二本鎖RNA とRNA 干渉を媒介する可溶性抽出物とを組み合わせる工程、それにより組み合わせを生じる;および
(b )二本鎖RNA が約21〜約23ヌクレオチド長のRNA にプロセスされる条件下でa )の組み合わせを維持する工程
を含む、約21〜約23ヌクレオチド長のRNA の作製方法、
〔10〕可溶性抽出物が合胞体胞胚葉ショウジョウバエ胚に由来するものである、〔9〕記載の方法、
〔11〕組み合わせから約21〜約23ヌクレオチドのRNA を単離する工程をさらに含む、〔9〕記載の方法、
〔12〕〔9〕記載の方法により作製された約21〜約23ヌクレオチドのRNA、
〔13〕(a )分解対象の遺伝子の配列に対応する二本鎖RNA とRNA 干渉を媒介する可溶性抽出物とを組み合わせる工程、それにより組み合わせを生じる;および
(b )二本鎖RNA が分解対象の遺伝子のmRNAのRNA 干渉を媒介する約21〜約23ヌクレオチドのRNA にプロセスされる条件下で(a )の組み合わせを維持する工程、それによりmRNAのRNA 干渉を媒介する約21〜約23ヌクレオチドのRNA を作製する、
を含む、分解対象の遺伝子のmRNAのRNA 干渉を媒介する約21〜約23ヌクレオチド長のRNA の作製方法、
〔14〕可溶性抽出物が合胞体胞胚葉ショウジョウバエ胚に由来するものである、〔13〕記載の方法、
〔15〕組み合わせから約21〜約23ヌクレオチドのRNA を単離する工程をさらに含む、〔13〕記載の方法、
〔16〕〔15〕記載の方法により作製された約21〜約23ヌクレオチドの単離されたRNA、
〔17〕(a )分解対象の遺伝子のmRNAを標的化する約21〜約23ヌクレオチドのRNA を細胞または生物に導入する工程;
(b )mRNAの分解が起こる条件下で(a )で作製された細胞または生物を維持する工程、それにより細胞または生物において遺伝子のmRNAのRNA 干渉を媒介する、
を含む、細胞または生物において遺伝子のmRNAのRNA 干渉を媒介する方法、
〔18〕(a )のRNA が化学合成されたRNA または天然に存在するRNA のアナログである、〔17〕記載の方法、
〔19〕前記遺伝子が細胞性mRNAまたはウイルスmRNAをコードする、〔17〕記載の方法、
〔20〕(a )遺伝子の配列に対応する二本鎖RNA とRNA 干渉を媒介する可溶性抽出物とを組み合わせる工程、それにより組み合わせを生じる;
(b )二本鎖RNA が約21〜約23ヌクレオチドのRNA にプロセスされる条件下で(a )で作製された組み合わせを維持する工程、それにより約21〜約23ヌクレオチドのRNA を作製する;
(c )(b )で作製された約21〜約23ヌクレオチドのRNA を単離する工程;
(d )細胞または生物に(c )単離されたRNA を導入する工程;および
(e )遺伝子のmRNAの分解が生じる条件下で(d )で作製された細胞または生物を維持する工程、それにより、細胞または生物において遺伝子のmRNAのRNA 干渉を媒介する、
を含む、RNA 干渉が生じる細胞または生物において遺伝子のmRNAのRNA 干渉を媒介する方法、
〔21〕可溶性抽出物が、合胞体胞胚葉ショウジョウバエ胚に由来するものである、〔20〕記載の方法、
〔22〕RNA がゲル電気泳動を用いて単離される、〔20〕記載の方法、
〔23〕(a )遺伝子のmRNAのRNA 干渉を媒介する約21〜約23ヌクレオチドのRNA を細胞または生物に導入する工程、それにより該RNA を含む細胞または生物を作製する、および(b )RNA 干渉が生じる条件下に、該RNA を含む細胞または生物を維持する工程、それにより該細胞または生物中の遺伝子のmRNAのRNA 干渉を媒介する、を含む、RNA 干渉が生じる細胞または生物において遺伝子のmRNAのRNA 干渉を媒介する方法、
〔24〕約21〜約23ヌクレオチドのRNA が、RNA 干渉を媒介する化学合成されたRNA またはRNA のアナログである、〔23〕記載の方法、
〔25〕遺伝子が細胞性mRNAまたはウイルスmRNAをコードするものである、〔23〕記載の方法、
〔26〕〔23〕記載の方法により生じたノックダウン細胞または生物、
〔27〕細胞または生物が疾患を模倣するものである、〔26〕記載のノックダウン細胞または生物、
〔28〕(a )分解対象の遺伝子のmRNAを標的化する約21〜約23ヌクレオチドのRNA を細胞または生物に導入する工程、それにより試験細胞または試験生物を作製する;
(b )遺伝子のmRNAの分解が生じる条件下で試験細胞または試験生物を維持する工程、それにより遺伝子のmRNAが分解する試験細胞または試験生物を作製する;および
(c )(b )において作製された試験細胞または試験生物の表現型を観察する工程、および任意に観察された表現型と適切な対照細胞または対照生物の表現型とを比較する工程、それにより遺伝子の機能に関する情報を提供する、
を含む、細胞または生物における遺伝子の機能の調査方法、
〔29〕(a )で導入されるRNA が、化学合成されているか、またはRNA 干渉を媒介するRNA のアナログである、〔28〕記載の方法、
〔30〕(a )遺伝子の配列に対応する二本鎖RNA とRNA 干渉を媒介する可溶性抽出物とを組み合わせる工程、それにより組み合わせを生じる;
(b )二本鎖RNA が約21〜約23ヌクレオチドのRNA にプロセシングされる条件下で(a )で生じた組み合わせを維持する工程、それにより約21〜約23ヌクレオチドのRNA が作製される;
(c )(b )で作製された約21〜約23ヌクレオチドのRNA を単離する工程;
(d )細胞または生物に(c )で単離されたRNA を導入する工程、それにより試験細胞または試験生物を作製する;
(e )遺伝子のmRNAの分解が生じる条件下で試験細胞または試験生物を維持する工程、それにより該遺伝子のmRNAが分解される試験細胞または試験生物を作製する;および
(f )(e )において作製される試験細胞または試験生物の表現型を観察する工程、および任意に観察された表現型と適切な対照の表現型とを比較する工程、それにより遺伝子の機能に関する情報を提供する、
を含む、細胞または生物における遺伝子の機能の調査方法、
〔31〕RNA が末端3’ヒドロキシル基を含有してなるものである、〔30〕記載の方法、
〔32〕可溶性抽出物が合胞体胞胚葉ショウジョウバエ胚に由来するものである、〔30〕記載の方法、
〔33〕RNA がゲル電気泳動を用いて単離される、〔30〕記載の方法、
〔34〕dsRNA を約21〜約23ヌクレオチドのRNA にプロセスするショウジョウバエ細胞の生化学成分および適切なキャリアを含有してなる組成物、
〔35〕約21〜約23ヌクレオチドのRNA により分解対象の遺伝子のmRNAを標的化する細胞の生化学成分を含有してなる組成物、
〔36〕分解対象のタンパク質のmRNAを標的化する約21〜約23ヌクレオチドのRNA を個体に投与することを含む、個体におけるタンパク質の存在に関する疾患または状態を治療する方法、
〔37〕約21〜約23ヌクレオチドのRNA が、化学合成されているか、またはRNA 干渉を媒介するRNA のアナログである、〔36〕記載の方法、
〔38〕(a )分解対象の遺伝子のmRNAを標的化する約21〜約23ヌクレオチドのRNA を細胞または生物に導入する工程;
(b ) mRNA の分解が生じる条件下で(a )の細胞または生物を維持する工程、
(c )(b )の細胞または生物に薬剤を導入する工程;および
(d )該薬剤が細胞または生物において効果を有するかどうかを決定する工程、ここで該薬剤が細胞または生物において効果を有さない場合、該薬剤が遺伝子産物または遺伝子産物を含む生物学的経路において作用する
を含む、薬剤が遺伝子産物に作用するかどうかを評価する方法、
〔39〕約21〜約23ヌクレオチドのRNA が、化学合成されているか、またはRNA 干渉を媒介するRNA のアナログである、〔38〕記載の方法、
〔40〕(a )分解対象の遺伝子のmRNAを標的化する約21〜約23ヌクレオチドのRNA を細胞または生物に導入する工程;
(b )mRNAの分解が生じる条件下で(a )の細胞または生物を維持する工程、それにより該遺伝子の発現の減少を生じる;および
(c )細胞または生物において遺伝子の減少した発現の効果を決定する工程、ここで減少した発現が効果を有する場合、遺伝子産物が薬物発見の標的である
を含む、遺伝子産物が薬物発見に適した標的であるかどうかを評価する方法、
〔41〕約21〜約23ヌクレオチドのRNA が、合成RNA またはRNA 干渉を媒介するRNA のアナログである、〔40〕記載の方法、
〔42〕RNA 干渉を媒介する内因性21〜23ヌクレオチドRNA 分子の配列決定により同定される遺伝子、
〔43〕RNA 干渉を媒介する約21〜約23ヌクレオチドのRNA および適切なキャリアを含有してなる医薬組成物、
〔44〕遺伝子がノックダウンされるべき細胞に、該遺伝子に対応するmRNAを標的化する約21〜約23ntのRNA を導入する工程および得られた細胞をRNAiが生じる条件下で維持する工程を含み、該遺伝子のmRNAの分解を生じ、それによりノックダウン細胞を作製する、ノックダウン細胞の作製方法、
〔45〕約21〜約23ヌクレオチドのRNA が、RNA 干渉を媒介する合成RNA またはRNA のアナログである、〔44〕記載の方法、
〔46〕分解対象の遺伝子の配列に対応するdsRNA 、該遺伝子に対応する標識mRNAおよびRNA 干渉を媒介する可溶性抽出物を組み合わせる工程、それにより組み合わせを生じる;dsRNA が分解される条件下で組み合わせを維持する工程および効率的に切断されるmRNA中の部位を同定する工程を含む、RNAiプロセスにより効率的に切断されるmRNA内の標的部位を同定する方法、
〔47〕〔46〕記載の方法によりmRNA内に同定される標的部位にわたる、RNAiを効率的に媒介する21〜23ntRNA を同定する方法、
〔48〕ゲル電気泳動を用いて単離された〔16〕記載のRNA、
〔49〕非変性法を用いて単離された〔16〕記載のRNA、
〔50〕非変性カラムクロマトグラフィーを用いて単離された〔16〕記載のRNA
に関する。
合胞体胞胚葉ショウジョウバエ胚に由来する無細胞系における遺伝子特異的、dsRNA 媒介性干渉が本明細書中に記載される。インビトロ系は、RNAiの分子基礎を分析するための遺伝的アプローチを補完する。本明細書中に記載されるように、RNAiの根底にある分子機構はショウジョウバエインビトロ系を用いて調査された。結果は、RNAiがATP 依存性であるが、mRNA転写からは切り離されていることを示した。これは、タンパク質合成がインビトロではRNAiには必要でないことを示した。RNAi反応において、dsRNA の両方の鎖(センスおよびアンチセンス)が約21〜約23ヌクレオチド(nt)長の小さなRNA 断片またはセグメントにプロセシングされる(21〜23nt長のマーカーに相当する配列決定ゲルにおける移動度を有するRNA 、任意に21〜23nt RNAと呼ばれる)。小RNA 断片へのdsRNA のプロセシングは、標的化mRNAを必要とはせず、このことは小RNA 種がdsRNA のプロセシングによって生じ、dsRNA 標的化mRNA分解の産物ではないことを示す。mRNAは、dsRNA を用いた同一性の領域内でのみ切断される。切断は、21〜23ヌクレオチド離れた部位で起こり、同じ間隔がdsRNA 自体について観察されており、dsRNA 由来の21〜23ヌクレオチド断片がmRNA切断をガイドしていることを示唆する。この精製された21〜23ntのRNA は、RNAiを媒介し、これらの断片がmRNA切断をガイドすることを確認する。
二本鎖(dsRNA )は、RNA 干渉(RNAi)として知られるプロセスを介してmRNAの配列特異的分解を行う。プロセスは、哺乳動物および他の脊椎動物の胚を含む、広範な生物において起こることが知られている。本明細書中に記載されるインビトロ系でショウジョウバエを用いて、dsRNA が21〜23ヌクレオチド(nt)長のRNA セグメントにプロセスされ、さらに、これらの21〜23ntフラグメントが精製され、ショウジョウバエ抽出物に戻された場合、それらはより長いdsRNA の非存在下でRNA 干渉を媒介する。従って、これらの21〜23ntフラグメントは、RNA 分解の配列特異的メディエータである。特定の長さのフラグメントでありうる分子シグナルは、RNAiに関与する細胞因子を漸加するためにこれらの21〜23ntフラグメントに存在するはずである。本発明は、これらの21〜23ntフラグメントおよび遺伝子機能を特異的に不活化するためのそれらの使用を包含する。これらのフラグメント(または同一もしくは類似した特性の組換え産生または化学合成のオリゴヌクレオチド)は、哺乳動物細胞における分解のために特定のmRNAの標的化を可能にする。RNAiを誘発するための哺乳動物細胞における長鎖dsRNA の使用は、おそらく、インターフェロン応答の有害な効果のために、通常実用的ではない。本発明の21〜23ntのフラグメントを用いて可能である、特定の遺伝子機能の特定の標的化は、機能的ゲノム適用および治療的適用に有用である。
実施例1に記載の遺伝子発現のdsRNA依存性サイレンシング(silencing) を反復(recapitulate)するインビトロショウジョウバエ胚溶解物の開発により、RNAiの生化学的解析が可能となった(Tuschl ら、Genes Dev.,13:3191-7 (1999))。インビトロ系では、センスまたはasRNAはそうではないが、dsRNAは、分解のために対応するmRNAを標的化するが、非関連対照mRNAの安定性には影響しない。さらに、溶解物中でのdsRNAのプレインキュベーションは、その標的mRNA分解のための活性を増強し、これは、dsRNAが、抽出物内のタンパク質と結合することにより、または二重結合性修飾により活性形態に変換されるにちがいないことを示唆する(Tuschl ら、Genes Dev.,13:3191-7 (1999))。
材料および方法
RNA
Rr−Luc mRNAは、pSP64プラスミドポリリンカー由来の25ntの5’非翻訳配列と、pSP64プラスミドポリリンカー配列の19ntおよび続く6ntのSac I部位からなる25ntの3’非翻訳配列とに隣接する926nt Rrルシフェラーゼコード配列から構成された。Pp−Luc mRNAは、Ppルシフェラーゼ停止コドンの直前にKpn I部位が導入された1653ntのPpルシフェラーゼコード配列を含有した。Ppコード配列は、21ntのpSP64プラスミドポリリンカーおよび続くショウジョウバエハンチバックmRNA由来の512ntの5’非翻訳領域(UTR)からなる5’非翻訳配列と、562ntハンチバック3’UTRおよび続く6ntのSac I部位からなる3’非翻訳配列とに隣接した。使用したハンチバック3’UTR配列は、インビボおよびインビトロでナノス応答エレメント(Nanos Response Element)の機能を破壊するG−U変異を6個含んだ。25ntポリ(A)テイルで終わる両方のレポーターmRNAは、転写されたプラスミド内にコードされた。Rr−Luc mRNAおよびPp−Luc mRNAの両方について、25ntのコードされたポリ(A)テイルが直後に続くNsi I部位で切断されるプラスミド鋳型からのラン・オフ転写により転写物を作製した。転写物がポリ(A)テイルで終わることを確実にするため、Nsi I切断転写物鋳型をdNTPの存在下でT4DNAポリメラーゼで切断(resect)した。SP6 mMessage mMachineキット(Ambion)をインビトロ転写に使用した。このキットを用い、得られた転写物の約80%を7−メチルグアノシンでキャップする。転写反応物にα−32P−UTPを含めることにより32P放射標識を行った。
20mM NaClを含む、ssRNAおよびasRNA(0.5μM)の10mM Tris−HCl(pH7.5)を1分間95℃まで加熱した後、冷却し、室温で12〜16時間アニーリングした。RNAを沈殿させ、溶解バッファー(下記)に再懸濁した。アニーリングをモニターするため、2%のアガロースゲルを含むTBEバッファー中でRNAを電気泳動させ、臭化エチジウムで染色した(Sambrookら、Molecular Cloning. Cold Spring Harbor Laboratory Press, Plainview, NY. (1989) )。
オレゴンRハエ(Oregon R fly)の0〜2時間目の胚を25℃の発光糖蜜(yeastedmolasses)寒天上に集めた。胚を4〜5分間50%(v/ v)漂白剤(bleach)中で絨毛膜除去(dechorionate)し、水洗し、ブロット乾燥し、低温Potter−Elvehjem組織摩砕器(Kontes)に移した。湿った胚1gあたり、5mMジチオトレイトール(DTT)および1mg/ml Pefabloc SC(Boehringer−Mannheim)を含む溶解バッファー(100mM酢酸カリウム、30mM HEPES−KOH、pH7.4、2mM酢酸マグネシウム)1ml中で胚を4℃で溶解させた。溶解物を、25分間、14500×gで4℃で遠心分離し、上清みを分割して液体窒素中で即座に凍結し、−80℃で保存した。
溶解物の調製および反応条件は、HussainおよびLeibowitz(HussainおよびLeibowitz 、Gene 46:13-23 (1986)) により記載されたものから誘導した。反応物は、50%(v/v)溶解物、mRNA(10〜50pMの最終濃度)、およびssRNA、asRNAまたはdsRNA(10nM最終濃度)を含む10%(v/v)溶解バッファーを含んだ。各反応物はまた、10mMクレアチンリン酸、10μg/mlクレアチンホスホキナーゼ、100μM GTP、100μM UTP、100μM CTP、500μM ATP、5μM DTT、0.1U/mL RNasin(Promega)、および100μMの各アミノ酸を含んだ。酢酸カリウムの最終濃度を100mMに調整した。標準的な条件のため、mRNAを添加する前に、反応物を氷上に集め(assemble)、次いで25℃で10分間予備インキュベートした。mRNAを添加した後、さらに60分間インキュベーションを続けた。10分間のプレインキュベーション工程は、図3A〜3Cおよび5A〜5Cの実験では省略した。4容量の1.25×Passive Lysis Buffer(Promega)で反応を停止させた。PpおよびRrルシフェラーゼ活性を、Dual−Luciferase Reporter Assay System(Promega)を用い、Monolight 2010 Luminometer(Analytical Luminescence Laboratory)で検出した。
32P−放射標識したmRNAを含む反応物を、40容量の2×PKバッファー(200mM Tris−HCl、pH7.5、25mM EDTA、300mM NaCl、2%w/vドデシル硫酸ナトリウム)の添加により消光(quench)させた。プロテイナーゼK( E.M.Merck;水に溶解) を最終濃度465μg/mlまで添加した。次いで、反応物を15分間65℃でインキュベートし、フェノール/クロロホルム/イソアミルアルコール(25:24:1)で抽出し、等容量のイソプロパノールで沈殿させた。ホルムアルデヒド/アガロース(0.8%w/v)ゲル(Sambrookら、Molecular Cloning. Cold Spring Harbor Laboratory Press, Plainview, NY. (1989) )での電気泳動により反応物を解析した。アガロースゲル[Nytran Plus膜(Amersham)上に真空下で乾燥] を画像用プレート(Fujix)に曝露することにより放射能を検出し、Fujix Bas 2000およびImage Gauge3.0(Fujix)ソフトウェアを用いて定量した。
未処置ウサギ網状赤血球溶解物(Ambion)および小麦麦芽抽出物(Ambion)の反応物を製造業者の指示書に従って構築した。mRNAの添加の前に、溶解物中でdsRNAを27℃(小麦麦芽)または30℃(網状赤血球溶解物)で10分間インキュベートした。
dsRNAがインビトロで遺伝子発現を特異的にブロックしうるか否かを評価するため、配列においてもルシフェリン基質特異性においても関連しない2つの異なるルシフェラーゼ遺伝子由来のレポーターmRNAを使用した:Renilla reniformis(ウミシイタケ)ルシフェラーゼ(Rr−Luc)およびPhoturis pennsylvanica(ホタル)ルシフェラーゼ(Pp−Luc)。一方の遺伝子から作製したdsRNAを該ルシフェラーゼmRNAを標的化するために使用し、他方のルシフェラーゼmRNAを、同じ反応で同時翻訳される内部対照とした。Rr−LucおよびPp−Luc遺伝子由来のポリメラーゼ連鎖反応産物の転写により約500bpのdsRNAを調製した。各dsRNAは翻訳開始点の約100bp下流から始まった(図1)。センス(ss)およびアンチセンス(as)RNAをインビトロで転写し、互いにアニーリングさせてdsRNAを作製した。Rr dsRNAおよびPp dsRNAを形成するために使用した個々のRr 501およびPp 505ntのasRNAおよびssRNAのネイティブ(native)ゲル電気泳動を行った。ssRNA、asRNAおよびdsRNAをそれぞれ、そのコグネイトmRNAの発現を特異的にブロックするが、非関連内部対照mRNAの発現は特異的にブロックしない能力について試験した。
方法および材料
インビトロRNAi
インビトロRNAi反応物および溶解物の調製は、反応物が、0.03g/mlクレアチンキナーゼ、25μMクレアチンリン酸(Fluka)および1mM ATPを含んだこと以外は、実施例1に記載の通りとした(Tuschl ら、Genes Dev.,13:3191-7 (1999))。各実験で、クレアチンリン酸を新たに500mMで水に溶解した。図2および3を除き、GTPを反応物から除外した。
Pp−luc mRNAおよびRr−luc mRNAならびにPp−dsRNAおよびRr−dsRNA(図6のdsRNA「B」を含む)を、先に先に記載(Tuschl ら、Genes Dev.,13:3191-7 (1999))のようにしてインビトロ転写により合成した。dsRNA「C」の転写鋳型を作製するため、5’センスRNAプライマーを、gcgtaatacgactcactataGAACAAAGGAAACGGATGAT( 配列番号:2) とし、3’センスRNAプライマーをGAAGAAGTTATTCTCCAAAA(配列番号:3)とし;5’asRNAプライマーをgcgtaatacgactcactataGAAGAAGTTATTCTCCAAAA(配列番号:4)とし、3’asRNAプライマーをGAACAAAGGAAACGGATGAT(配列番号:5)とした。dsRNA「A」のためには、5’センスRNAプライマーを、gcgtaatacgactcactataGTAGCGCGGTGTATTATACC( 配列番号:6) とし、3’センスRNAプライマーをGTACAACGTCAGGTTTACCA(配列番号:7)とし;5’asRNAプライマーをgcgtaatacgactcactataGTACAACGTCAGGTTTACCA(配列番号:8)とし、3’asRNAプライマーをGTAGCGCGGTGTATTATACC(配列番号:9)とした(小文字はT7プロモーター配列)。
溶解物を10分間25℃で2mMグルコースおよび0.1U/mlヘキソキナーゼ(Sigma)とともにインキュベートすることによりATPを枯渇させた。タンパク質合成インヒビターを、Sigma社から購入し、250倍濃縮原液として無水エタノールに溶解した。反応物におけるインヒビターの最終濃度は、アニソマイシン53mg/ml;シクロヘキシミド100mg/ml;クロラムフェニコール100mg/mlとした。相対タンパク質合成を、RNAi反応においてRr−luc mRNAの翻訳により産生されたRrルシフェラーゼタンパク質の活性を1時間後に先に記載(Tuschl ら、Genes Dev.,13:3191-7 (1999))のようにして測定することにより測定した。
内部α−32P−ATP標識したdsRNA(505bp Pp−lucまたは501bp Rr−luc)または7−メチル−グアノシンキャップRr−lucアンチセンスRNA(501nt)を5nMの最終濃度で、標準的な条件下、2時間、ショウジョウバエ溶解物中で非標識mRNAの存在下または非存在下でインキュベートした。2×プロテイナーゼKバッファーの添加により反応を停止させ、先に記載(Tuschl ら、Genes Dev.,13:3191-3197 (1999)) のようにして除タンパクした。15%または18%ポリアクリルアミドシークエンシングゲル内での電気泳動により生成物を解析した。α−32P−ATP標識した501nt Rr−lucセンスRNAおよびasRNAの完全RNアーゼT1消化により長さ標準品を作製した。
内部α−32P−ATP標識したdsRNA(5nM)を、標準的な条件で2時間、ショウジョウバエ溶解物中でインキュベートした。除タンパクした後、試料を12%シークエンシングゲル上に供し、完全長のdsRNAを21〜23nt産物から分離した。0.3M NaCl中で一晩、ゲル切片からRNAを溶出し、エタノール沈殿させ、遠心分離により回収し、29μlの水中に再溶解した。RNAを、ヌクレアーゼP1(水中8μl RNAを含有する10μl反応物、30mM KOAc、pH5.3、10mM ZnSO4 、10μgまたは3単位のヌクレアーゼP1、3時間、50℃)でヌクレオシド5−リン酸塩に加水分解した。試料(1ml)を非放射活性5−モノヌクレオチド[0.05O.D.単位(A260 )のpA、pC、pG、pIおよびpU]とともにセルロースHPTLCプレート(EM Merck)上で同時スポットし、一次元においてイソ酪酸/25%アンモニア/水(66/1/33、v/v/v)および二次元において0.1Mリン酸ナトリウム、pH6.8/硫酸アンモニウム/1−プロパノール(100/60/2,v/w/v;Silberklang ら、1979)で分離した。非放射活性内部標準の移動をUVシャドウイング(shadowing) により測定した。
RNAiはATPを必要とする
実施例1において記載したように、ショウジョウバエ胚溶解物は、RNAiを忠実に反復する(Tuschl ら、Genes Dev.,13:3191-7 (1999))。あらかじめ、標的化mRNAからのルシフェラーゼタンパク質の合成を測定することによりdsRNA媒介性遺伝子スプライシングをモニターした。したがって、これらのRNAi反応は、mRNAの効率的な翻訳に必要なATP再生系を含んだ。ATPが実際にRNAiに必要であるか否かを試験するため、ATPをADPに変換させるヘキソキナーゼおよびグルコースで処理することにより溶解物からATPを枯渇させ、32P−放射標識したウミシイタケルシフェラーゼ(Rr−luc)mRNAの運命を追跡することにより直接RNAiをモニターした(図6)。ヘキソキナーゼおよびグルコースでの処理により、溶解物中の内在ATPレベルが250μMから10μM未満に低下した。ATP再生は、外来クレアチンリン酸およびクレアチンキナーゼの両方を必要とし、高エネルギーリン酸塩をクレアチンリン酸からADPに移動させるために作用する。ATP枯渇抽出物にクレアチンリン酸またはクレアチンキナーゼのいずれかを別個に補充すると、RNAiは観察されなかった。したがって、RNAiはインビトロでATPを必要とする。ATP枯渇溶解物を含有する反応物にATP、クレアチンリン酸およびクレアチンキナーゼをすべて一緒に添加した場合、Rr−luc mRNAのdsRNA依存性分解が回復した(図6)。クレアチンリン酸およびクレアチンキナーゼの両方が存在するならば、外来ATPの添加は該枯渇溶解物での効率的なRNAiには必要でなく、これは、アデノシンヌクレオチドの内在濃度(250mM)がRNAiを補助するのに充分であることを示す。ホタルルシフェラーゼ(Pp−luc)mRNAを伴うRNAiもまた、ATP依存性である。
ATP に対する必要条件は、RNAiがmRNA翻訳の高エネルギー依存プロセスに連結しうることを示唆する。この可能性を試験するために、タンパク質合成インヒビターの有りおよび無しの標準RNAi反応物中で示した時間のインキュベーション後、5'-32P- 放射能標識Pp-luc mRNA の変性アガロースゲル解析を調製することにより、タンパク質合成の様々なインヒビターを反応物に添加した。真核生物翻訳インヒビターのアニソマイシン、最初のペプチド結合形成のインヒビター、シクロヘキシミド、ペプチド鎖伸長のインヒビター、およびピューロマイシン、翻訳のプレ成熟終結を生じるtRNA模倣物(Cundliffe, Antibiotic Inhibitors of Ribosome Function. The Molecular Basis of Antibiotic ActionにおけるE. Gale, E. Cundliffe, P. Reynolds, M. Richmond およびM. Warning編(New York: Wiley),pp.402-547.(1981))を試験した。これらのインヒビターの各々は、ショウジョウバエ溶解物において1,900 倍より多くタンパク質合成を減少させた(図7A)。対照的に、クロラムフェニコール、ショウジョウバエミトコンドリアタンパク質合成のインヒビター(Page およびOrr-Weaver, Dev. Biol., 183:195-207(1997))は、溶解物において翻訳に対して効果を持たなかった(図7A)。アニソマイシン、シクロヘキシミド、またはクロラムフェニコールの存在にかかわらず、RNAiは通常の効率で行なわれた。ピューロマイシンはまた、効率的なRNAiを乱さなかった。したがって、タンパク質合成はインビトロでのRNAiに必要でない。
25nt長のRNA は、植物において転写後遺伝子サイレンシングを受ける遺伝子のセンスおよびアンチセンス鎖から生じる(Hamilton およびBaulcombe, Science, 286:950-2(1999))。均一に32P-放射能標識したdsRNA の2時間のインキュベーションにおいて変性アクリルアミドゲル解析産物を形成させ、標的mRNAの存在または非存在下で標準RNAi条件下で溶解物中でasRNA をキャップした。dsRNA がまた、小RNA 断片にプロセスされることが見出された。溶解物中でインキュベートした場合、501bp Rr-dsRNAおよび505bp Pp-dsRNAの両方の約15%の投入放射能が21〜23ntRNA 断片に見られた。dsRNA は、500bp 長より長いため、断片の15%の収率は、多数の21〜23nt RNAが各全長dsRNA 分子から作製されることを意味する。他の安定な産物は検出されなかった。両方の鎖を均等に32P-放射能標識したdsRNA から、小さいRNA 種を作製した。dsRNA 由来の21〜23nt RNAの形成が、対応するmRNAの存在を必要としなかったことは、小さいRNA 種が、dsRNA-標的化mRNA分解の産物としてよりむしろdsRNA のプロセシングにより生じることを証明している。22ヌクレオチドは、A-型RNA-RNA ヘリックスの2つのターンに対応することが注目された。
mRNAを5'-7- メチル- グアノシンキャップ内で32P-放射能標識した場合、安定な5'崩壊産物がRNAi反応の間に蓄積した。かかる安定な5'崩壊産物が、Pp-lucおよびRr-luc mRNA の両方に対して、それらのコグネイト(cognate)dsRNAとともにインキュベートされた場合に観察された。以前、asRNA がdsRNA の代わりに使用される場合、有効なRNAiが生じないことが報告された(Tuschl ら、Genes Dev., 13:3191-7(1999))。にもかかわらず、バッファーとよりasRNA とインキュベートした場合に、mRNAはあまり安定でなかった(図8Aおよび8B)。これは、Rr-luc mRNA に対して特に明らかであった:溶解物中での3時間のインキュベーション後、約90%のRNA が完全なままであったが、asRNA を添加した場合約50%のみであった。dsRNA を添加した場合、5 %未満が残った。興味深いことに、asRNA により生じたmRNA安定性における減少は、dsRNA を用いるRNAi反応に特徴的な少量の安定な5'- 崩壊産物の形成により伴われた。この知見は、mRNAとインキュベートした場合に(上記参照)、少量の21〜23nt産物がasRNA から形成されるという観察に匹敵し、asRNA は効率が悪いにもかかわらず、RNAi経路に入りうるという考えに説得力を与える。
mRNA切断部位を、約100nt のRr-luc配列から移した3つの異なるdsRNA 、「A」、「B」および「C」を用いて試験した。3つのdsRNA 、「A」「B」および「C」のそれぞれとの、またはバッファー(Φ)との所定時間のRr-luc mRNA のインキュベーションを行なった後に生じた安定な5'- 切断産物の変性アクリルアミド- ゲル解析を行なった。Rr-luc mRNA 配列と比べたこれらの位置を図9 に示す。5'- キャップ内で32P-放射能標識したRr-luc mRNA を有する標準RNAi反応物中で3つのdsRNA の各々をインキュベートした。dsRNA の不在下において、溶解物中の3時間のインキュベーション後でさえ、mRNAとして安定な5'- 切断産物は検出されなかった。対照的に、20分のインキュベーション後、3つのdsRNA の各々は、特定のdsRNA に特徴的なmRNA切断産物のセットに対応するはしご状のバンドを作製する。各dsRNA に対して安定な5'mRNA切断産物は、dsRNA に対応したRr-luc mRNA の領域に限定された( 図9 および10) 。dsRNA の「A」に対して、5'- 切断産物の長さは、236 〜約750nt 未満の範囲であった;dsRNA の「A」は、Rr-luc mRNA のヌクレオチド233 〜729 にわたる。dsRNA の「B」とのmRNAのインキュベーションは、150 〜約600nt の長さの範囲のmRNA 5'-切断産物を生じた;dsRNA の「B」は、mRNAのヌクレオチド143 〜644 にわたる。最後に、dsRNA の「C」は、66〜約500nt の長さのmRNA切断産物を生じた。このdsRNA は、Rr-luc mRNA のヌクレオチド50〜569 にわたる。したがって、dsRNA は、全細胞mRNAプールからどのmRNAが分解されるかを選択するRNAi反応に対して特異性を与えるだけでなく、mRNA配列の切断の正確な位置もまた決定する。
RNAiの機構においてさらなる洞察を得るために、3つのdsRNA の各々に対するいくつかのmRNA切断部位の位置をマップした(図10)。上記5'-切断産物のサブセットの高分解能変性アクリルアミド- ゲル解析を行なった。注目すべきことに、ほとんどの切断は、21〜23ntの間隔で生じた(図10)。dsRNA が、21〜23nt RNA種にプロセスされるという本発明者らの観察、ならびに25nt RNAが植物における転写後遺伝子サイレンスと関係づけられるというHamiltonおよびBaulcombe の知見(Hamilton およびBaulcombe, Science, 286:950-2(1999))を考慮すれば、この間隔は、特に著しい(striking)。本発明者らが位置決定をした16個の切断部位のなかで(dsRNAの「A」に対して2、dsRNA の「B」に対して5、dsRNA の「C」に対して9)、2個を除いた全てが21〜23nt間隔を反映する。2つの例外的な切断の1つは、dsRNA 「C」により作製された弱い切断部位であった(図10に中空青丸で示した)。この切断は、次の切断部位の32nt 5' に生じた。他方の例外は、特に興味深い。4つの切断が21〜23ntの間隔を保った後、dsRNA の「C」は、前の切断部位のちょうど9nt 3'のmRNAの切断を生じた(図10の赤色の矢じり)。この切断は、7個のウラシル残基のランを生じ、切断のための定規を「リセット」するようである;次の切断部位は、例外部位の21〜23nt 3' であった。本発明者らがマップした次の3つの切断部位もまた、21〜23ntの間隔で離れていた。不思議なことに、3つの異なるdsRNA により生じた16個の切断部位のなかで、14個がウラシル残基で生じた。この知見の意味は理解されていないが、mRNA切断が、21〜23nt間隔を測定し、ウラシルで切断に対する配列選択を有するプロセスにより決定されることを示唆する。結果は、溶解物中の約500bp のdsRNA のインキュベーションにより生じた21〜23ntのRNA 種が、アクリルアミドゲルから単離され、全長dsRNA の代わりに新しいRNAi反応物に添加された場合、インビトロで配列特異的干渉を生じたことを示す。
理論に束縛されることは望まないが、本明細書に記載された生化学的データは、C.エレガンスおよびアカパンカビ属における最近の遺伝子実験と共に(Cogoni およびMacino, Nature, 399:166-9(1999);Grishok ら、Science, 287:2494-7(2000);Ketting ら、Cell, 99:133-41(1999);Tabaraら、Cell,99:123-32(1999)) 、どのようにdsRNA がmRNAを破壊のために標的化するのかに関するモデルを示唆する(図11)。このモデルでは、C.エレガンス遺伝子座rde-1 およびrde-4 などの遺伝子に関与するようなプロセスにおいて、dsRNA は最初に21〜23nt長の断片に切断される。得られた断片(おそらくRNAi特異的タンパク質に結合した短いasRNA )は、次にmRNAと対を形成し、mRNAを切断するヌクレアーゼを漸加するであろう。代替的には、鎖交換は、mRNAに類似する21〜23ntのdsRNA 断片を一時的に有するタンパク質-RNA複合体で生じ得る。断片化に続くdsRNA の二本鎖の分離は、ATP-依存性RNA ヘリカーゼにより援助され得、観察された21〜23nt RNA作製のATP 増加を説明する。
溶解物中の500bp dsRNA のインキュベーション反応からの21〜23nt断片の単離
二本鎖RNA (500bp由来) をショウジョウバエ胚溶解物中10nMの濃度で本明細書に記載の標準条件下に3 時間25℃にてインキュベートした。試料の除タンパク後、21〜23ntの反応産物を未プロセスdsRNA から変性ポリアクリルアミド(15 %) ゲル電気泳動により分離した。非放射能標識21〜23nt断片の検出のために、放射能標識dsRNA とのインキュベーション反応を同じゲルの別のレーンに負荷した。非放射活性21〜23nt断片を含むゲルスライスを切り出し、ゲルスライスから21〜23nt断片を0.4ml の0.3M NaCl で4℃で一晩かけて溶出した。エタノール沈殿および遠心分離により、RNA を上清から回収した。10μl の溶解バッファーにRNA ペレットを溶解させた。対照として、21〜23ntバンドよりわずかに高いゲルスライスおよび低いゲルスライスもまた切り出し、同じ溶出および沈殿手順に供した。インキュベートしていないdsRNA もまた15%ゲル上に負荷し、21〜23nt断片に対応するゲルスライスを切り出して、溶出した。対照実験由来の全部のペレットを10μl の溶解バッファーに溶解させた。溶出によるゲルスライス由来の回収の間のRNA の損失は、約50%である。
溶出21〜23マーまたは対照RNA 溶液の1 μl を、標準10μl RNAiインキュベーション反応に使用した(上記)。標的および対照mRNAの添加の前に、21〜23マーを反応混合物を含む溶解物中で10分または30分間プレインキュベートした。これらのRNA 上の特異的なシグナルの存在のために、プレインキュベートの間に、RNA 干渉を伴うタンパク質は21〜23マーと再会合しうる。インキュベートをさらに1時間続け、標的および対照mRNAの翻訳を可能にした。受動(passive) 溶解バッファー(Promega )の添加により反応をクエンチさせ、ルシフェラーゼ活性を測定した。RNA を含まないバッファー対照により標準化された対照ルシフェラーゼ活性に対する標的の比として、RNA 干渉が表される。標的遺伝子の特異的な抑制を10分または30分のいずれかのプレインキュベーションを用いて観察した。この抑制は再現性があり、対照に対する標的の相対比は2 〜3 倍低下した。対照として単離されたRNA 断片は、特異的な干渉を示さなかった。対照的に、5 nMの500bp dsRNA のインキュベーション(10分のプレインキュベーション)は、標的遺伝子に対する対照の相対比が約30倍の傾向がある。
精製21〜23nt RNA断片により媒介されるRNAiの観察に一致して、投入21〜23nt RNAの35%がかかるインキュベーション反応において3 時間より多く維持することを見出した。このことは、細胞性因子(factor)が除タンパクした21〜23nt断片に会合し、機能的なmRNA分解分子を再構築することを示唆している。これらの21〜23nt断片に結合するシグナル、またはそれらの起こり得る二本鎖の性質または特異的な長さは、この観察の原因であるようである。過ヨウ素酸塩処理およびβ脱離に続く配列決定ゲル上での変化した移動度により証明されるように、21〜23nt断片は末端3'ヒドロキシル基を有する。
50ナノモルの二本鎖RNA(実施例1に記載された501bp Rr-luc dsRNA)を溶解物を有するインビトロ反応物1ml 中で25℃にてインキュベートした(実施例1参照)。次に、2×PKバッファーの添加により反応を停止させ(実施例1参照)、プロテイナーゼKを最終濃度が1.8 μg/μl になるまで添加した。反応物をさらに1 時間25℃でインキュベートし、フェノール抽出し、次に3 容量のエタノールを用いてRNA を沈澱させた。エタノール沈澱物を遠心分離により回収し、100 μlの溶解バッファー中でペレットを再懸濁させ、溶解バッファー中0.75ml/ 分でSuperdex HR 200 10/30 ゲル濾過カラム(Pharmacia )ランに適用した。200 μlの画分をカラムから回収した。3Mの酢酸ナトリウム20μl およびグリコーゲン20μg を各画分に添加し、3 容量のエタノールを用いた沈澱によりRNA を回収した。沈殿物を30μl の溶解バッファーに再懸濁した。32P-標識投入RNA の画分化後のカラムプロフィールを、図13A に示す。
方法
RNA 調製
Expedite RNAホスホロアミダイトおよびチミジンホスホロアミダイト(Proligo, Germany)を用いて、21nt RNAを化学的に合成した。合成オリゴヌクレオチドを脱タンパクし、ゲル精製し(Elbashir, S.M., Lendeckel, W. & Tuschl, T., Genes & Dev. 15, 188-200(2001))、次いでSep-Pak C18 カートリッジ(Waters, Milfold, MA, USA)精製を行なった(Tuschl, t.,ら、Biochemistry, 32:11658-11668(1993) )。GL2 (Acc.X65324)およびGL3 ルシフェラーゼ(Acc.U47296)を標的化するsiRNA 配列は、開始コドンの最初のヌクレオチドに関連するコード領域153-173 に対応し、RL(Acc.AF025846)を標的化するsiRNA は、開始コドン後の領域119-129 に対応した。PCR 産物由来のT7 RNAポリメラーゼを用いてより長いRNA を転写し、次いでゲルおよびSep-Pak 精製を行なった。49および484bp のGL2 またはGL3 dsRNA は、翻訳開始に関連する113-161 位および113-596 位にそれぞれ対応した;50および501bp のRL dsRNAは、118-167 位および118-618 位にそれぞれ対応した。ヒト化GFP(hG) を標的化するdsRNA 合成に対するPCR テンプレートをpAD3から増幅し(Kehlenbach,R.H.ら、J. Cell Biol., 141:863-874(1998)) 、それにより50および501bp hG dsRNAは、開始コドンに対して118-167 位および118-618 位にそれぞれ対応した。
10%FBS 、100 ユニット/ml のペニシリン、および100 μg/mlのストレプトマイシンを補充したSchneider のショウジョウバエ培地(Life Technologies) 中で、S2細胞を25℃で増殖させた。10%FBS 、100 ユニット/ml のペニシリン、および100 μg/mlのストレプトマイシンを補充したダルベッコ改変イーグル培地中で37℃で293 、NIH/3T3 、HeLa S3 、COS-7 細胞を増殖させた。指数増殖を維持するために、細胞を定期的に継代した。約80%コンフルエンシーでのトランスフェクションの24時間前に、哺乳動物細胞をトリプシン処理し、抗生物質を含まない新しい培地を用いて1:5 に希釈し(1-3×105 細胞/ml)、24ウェルプレートに移した(500μl/ウェル) 。S2細胞は、分裂前にトリプシン処理しなかった。リポフェクトアミン2000試薬(Life Technologies) を用いて、接着細胞株に対して製造業者により記載されたようにトランスフェクションを行なった。ウェル当たり、1.0 μg のpGL2-Control(Promega) またはpGL3-Control(Promega) 、1 μg のpRL-TK(Promega) 、および0.28μg のsiRNA 二重鎖またはdsRNA をリポソームに配合したものを適用した;最終容量は、ウェル当たり600 μl であった。トランスフェクション後20時間細胞をインキュベートし、その後健康であるように見えた。次にルシフェラーゼ発現を、二重ルシフェラーゼアッセイ(Promega) を用いてモニターした。1.1 μg のhGFP- コードpAD322および0.28μg のinvGL2 siRNAの共トランスフェクション後、哺乳動物細胞株に対して蛍光顕微鏡によりトランスフェクション効率を測定し、70〜90%であった。レポータープラスミドをXL-1 Blue(Strategene)中で増幅し、Qiagen EndoFree Maxi Plasmid Kitを用いて精製した。
RNA 干渉(RNAi)は、サイレンス遺伝子に対する配列において二本鎖RNA (dsRNA) 相同により開始される、動物および植物における配列特異的な転写後遺伝子サイレンシングプロセスである(Fire,A., Trends Genet., 15:358-363(1999);Sharp,P.A. & Zamore,P.D., Science, 287:2431-2433(2000);Sijen, T. & Kooter,J.M., Bioessays, 22:520-531(2000);Bass,B.L., Cell, 101:235-238(2000);Hammond, S.M.ら、Nat. Rev, Genet., 2:110-119(2001))。配列特異的mRNA分解のメディエータは、より長いdsRNA6-10 由来のRNase III 切断により生じた21および22ntの小さい干渉RNA(siRNA)である(Hamilton,A.J. & Baulcombe,D.C.,Science, 286:950-952(1999);Hammond,S.M.ら、Nature, 404:293-296(2000);Zamore,P.D. ら、Cell, 101:25-33(2000);Bernstein,E.ら、Naature, 409:363-366(2001);Elbashir, S.M. ら、Genes & Dev.,15:188-200(2001))。本明細書に示されるように、21nt siRNA二重鎖は、ヒト胎児腎臓(293) およびHeLa細胞を含む多数の哺乳動物組織培養物においてレポーター遺伝子発現を特異的に抑制しうる。50または500bp dsRNA と対照的に、siRNA はインターフェロン応答を活性化しない。これらの結果は、siRNA 二重鎖が哺乳動物細胞における遺伝子機能の配列特異的不活性化のための一般的なツールであることを示している。
Claims (44)
- 単離された二本鎖RNAであって、該単離された二本鎖RNAの各々の鎖は、21〜23ヌクレオチド長であり、該単離された二本鎖RNAの一方の鎖は、遺伝子のmRNAに対して完全な配列相補性を有し、該単離された二本鎖RNAは、mRNAの切断を引き起こすことによって遺伝子のmRNAのRNA干渉を媒介し、切断は、該単離された二本鎖RNAとの配列相補性の領域内で引き起こされる、単離された二本鎖RNA。
- mRNAが、哺乳動物細胞性mRNAまたはウイルスmRNAである、請求項1記載の単離された二本鎖RNA。
- RNAが末端3'ヒドロキシル基を含んでなる請求項1記載の単離された二本鎖RNA。
- RNAが化学的に合成されたRNAである、請求項1記載の単離された二本鎖RNA。
- RNA干渉が起こる細胞または生物において遺伝子のmRNAのRNA干渉を媒介するための組成物の調製のための二本鎖RNAの使用であって、該二本鎖RNAの各々の鎖は、21〜23ヌクレオチド長であり、該二本鎖RNAの一方の鎖は、遺伝子のmRNAに対して完全な配列相補性を有し、該二本鎖RNAを、細胞または生物に導入し、得られた細胞または生物を、RNA干渉が起こる条件下で維持する場合に、該二本鎖RNAは、細胞または生物の遺伝子のmRNAのRNA干渉を媒介する、使用。
- 該二本鎖RNAは、化学的に合成されたRNAまたはRNA干渉を媒介するRNAのアナログである、請求項5記載の使用。
- 遺伝子が細胞性mRNAまたはウイルスmRNAをコードするものである、請求項5記載の使用。
- (a) 二本鎖RNAを、細胞(インサイチュにおいて見られるヒト細胞を除く)または非ヒト生物に導入する工程、ここで、該二本鎖RNAの各々の鎖は、21〜23ヌクレオチド長であり、該二本鎖RNAの一方の鎖は、遺伝子のmRNAに対して完全な配列相補性を有し、該二本鎖RNAは、遺伝子のmRNAのRNA干渉を媒介する;および
(b) 該細胞または非ヒト生物を、RNA干渉が起こる条件下で維持し、それにより該細胞または非ヒト生物において遺伝子のmRNAのRNA干渉を媒介する工程、
を含む方法により作製される、ノックダウン細胞(インサイチュにおいて見られるヒト細胞を除く)または非ヒト生物。 - 細胞または生物が疾患を模倣するものである、請求項8記載のノックダウン細胞(インサイチュにおいて見られるヒト細胞を除く)または非ヒト生物。
- (a) 二本鎖RNAを細胞(インサイチュにおいて見られるヒト細胞を除く)または非ヒト生物に導入し、それにより試験細胞または試験生物を作製する工程、ここで、該二本鎖RNAの各々の鎖は21〜23ヌクレオチド長であり、該二本鎖RNAの一方の鎖は、遺伝子のmRNAに対して完全な配列相補性を有し、該二本鎖RNAは、mRNAの切断を引き起こすことによってRNA干渉を媒介する;
(b) RNA干渉が起こる条件下で試験細胞または試験生物を維持し、それにより遺伝子のmRNAが分解された試験細胞または試験生物を作製する工程;ならびに
(c) (b)において作製された試験細胞または試験生物の表現型を観察し、および任意に観察された表現型と適切な対照細胞または対照生物の表現型とを比較し、それにより遺伝子の機能に関する情報を提供する工程、
を含む、細胞(インサイチュにおいて見られるヒト細胞を除く)または非ヒト生物における遺伝子の機能を調査する方法。 - (a)で導入されるRNAが、化学的に合成されているか、またはRNA 干渉を媒介するRNAのアナログである、請求項10記載の方法。
- RNAが末端3'ヒドロキシル基を含んでなるものである、請求項10記載の方法。
- 単離された二本鎖RNAを含む、個体におけるタンパク質の存在に関する疾患または状態を治療するための組成物であって、該単離された二本鎖RNAの各々の鎖は21〜23ヌクレオチド長であり、該単離された二本鎖RNAは、タンパク質のmRNAのRNA干渉を媒介し、該単離された二本鎖RNAの一方の鎖は、タンパク質のmRNAに対して完全な配列相補性を有し、該単離された二本鎖RNAは、mRNAの切断を引き起こすことによってRNA干渉を媒介し、切断は、該単離された二本鎖RNAとの配列相補性の領域内で引き起こされる、組成物。
- mRNAが哺乳動物細胞性mRNAである、請求項13記載の組成物。
- 該単離された二本鎖RNAが化学的に合成されたものである、請求項13記載の組成物。
- (a) 二本鎖RNAを細胞試料または非ヒト生物に導入する工程、ここで、該二本鎖RNAの各々の鎖は21〜23ヌクレオチド長であり、該二本鎖RNAの一方の鎖は、遺伝子のmRNAに対して完全な配列相補性を有し、該二本鎖RNAは、mRNAの切断を引き起こすことによってmRNAのRNA干渉を媒介する;
(b) mRNAの分解が生じる条件下で(a)の細胞試料または非ヒト生物を維持する工程;
(c) (b)の細胞試料または非ヒト生物に薬剤を導入する工程;および
(d) 該薬剤が細胞試料または非ヒト生物において効果を有するかどうかを決定する工程、ここで該薬剤が細胞試料または非ヒト生物において効果を有さない場合、該薬剤が遺伝子産物または遺伝子産物が関与する生物学的経路において作用する、
を含む、薬剤が遺伝子産物に作用することを検証するための方法。 - 該二本鎖RNAが化学的に合成されたものである、請求項16記載の方法。
- (a) 二本鎖RNAを細胞試料または非ヒト生物に導入する工程、ここで、該二本鎖RNAの各々の鎖は21〜23ヌクレオチド長であり、該二本鎖RNAの一方の鎖は、遺伝子のmRNAに対して完全な配列相補性を有し、該二本鎖RNAは、mRNAの切断を引き起こすことによってmRNAのRNA干渉を媒介する;
(b) mRNAの分解が生じる条件下で(a)の細胞試料または非ヒト生物を維持し、該遺伝子の発現の減少を生じる工程;および
(c) 細胞試料または非ヒト生物における遺伝子の減少した発現の効果を決定する工程、ここで減少した発現が効果を有する場合、遺伝子産物が薬物発見の標的である、
を含む、遺伝子産物が薬物発見に適した標的であるかどうかを評価する方法。 - 該二本鎖RNAが化学的に合成されたものである、請求項18記載の方法。
- 二本鎖RNA、ここで、該二本鎖RNAの各々の鎖は21〜23ヌクレオチド長であり、該二本鎖RNAの一方の鎖は、mRNAに対して完全な配列相補性を有し、該二本鎖RNAは、mRNAの切断を引き起こすことによってRNA干渉を媒介する、および
適切な担体
を含有してなる医薬組成物であって、切断は、該二本鎖RNAとの配列相補性の領域内で引き起こされ、該mRNAは哺乳動物細胞性mRNAである、医薬組成物。 - 遺伝子がノックダウンされるべき細胞試料に、二本鎖RNAを導入する工程、ここで、該二本鎖RNAの各々の鎖は21〜23ヌクレオチド長であり、該二本鎖RNAの一方の鎖は、遺伝子のmRNAに対して完全な配列相補性を有し、該二本鎖RNAは、mRNAの切断を引き起こすことによってRNA干渉を媒介する;および
得られた細胞試料を、RNA干渉が起こる条件下で維持し、該遺伝子のmRNAの分解を生じさせ、それによりノックダウン細胞を作製する工程、
を含む、ノックダウン細胞を作製する方法。 - 該二本鎖RNAが、合成RNAまたはRNA干渉を媒介するRNAのアナログである、請求項21記載の方法。
- 単離された二本鎖RNAであって、該単離された二本鎖RNAの各々の鎖は21〜23ヌクレオチド長であり、該単離された二本鎖RNAの一方の鎖は、mRNAに対して完全な配列相補性を有し、該単離された二本鎖RNAは、mRNAの切断を引き起こすことによってRNA干渉を媒介し、切断は、該二本鎖RNAとの配列相補性の領域内で引き起こされ、該mRNAは哺乳動物細胞性mRNAである、単離された二本鎖RNA。
- 末端3'ヒドロキシル基を含んでなる請求項23記載の単離された二本鎖RNA。
- 単離された二本鎖RNAであって、該単離された二本鎖RNAの各々の鎖は21〜23ヌクレオチド長であり、該二本鎖RNAは、化学的に合成されたRNAであり、該二本鎖RNAの一方の鎖は、mRNAに対して完全な配列相補性を有し、該二本鎖RNAは、mRNAの切断を引き起こすことによってRNA干渉を媒介し、切断は、該二本鎖RNAとの配列相補性の領域内で引き起こされる、単離された二本鎖RNA。
- mRNAが哺乳動物細胞性mRNAである、請求項25記載の単離された二本鎖RNA。
- 単離された二本鎖RNA、ここで、該単離された二本鎖RNAの各々の鎖は21〜23ヌクレオチド長であり、該単離された二本鎖RNAの一方の鎖は、mRNAに対して完全な配列相補性を有し、該単離された二本鎖RNAは、mRNAの切断を引き起こすことによってRNA干渉を媒介する、および
適切な担体
を含む組成物であって、切断は、該RNAとの配列相補性の領域内で引き起こされる、組成物。 - mRNAが哺乳動物細胞性mRNAである、請求項27記載の組成物。
- 担体および単離された二本鎖RNAを含む組成物であって、該単離された二本鎖RNAの各々の鎖は21〜23ヌクレオチド長であり、該単離された二本鎖RNAの一方の鎖は、mRNAに対して完全な配列相補性を有し、該単離された二本鎖RNAは、mRNAのRNA干渉を媒介し、該単離された二本鎖RNAは、21〜23ヌクレオチド長の断片に切断された二本鎖RNAから得られる、組成物。
- mRNAが哺乳動物細胞性mRNAである、請求項29記載の組成物。
- mRNAがヒトmRNAである、請求項23または25記載の単離された二本鎖RNA。
- 二本鎖RNAのアナログであって、該二本鎖RNAのアナログの各々の鎖は21〜23ヌクレオチド長であり、該二本鎖RNAのアナログの一方の鎖は、mRNAに対して完全な配列相補性を有し、該二本鎖RNAのアナログは、mRNAの切断を引き起こすことによってRNA干渉を媒介し、切断は、該二本鎖RNAのアナログとの配列相補性の領域内で引き起こされ、該二本鎖RNAのアナログの1つ以上のヌクレオチドは、天然に存在しないヌクレオチド、またはデオキシリボヌクレオチド、または非標準ヌクレオチドである、二本鎖RNAのアナログ。
- mRNAが哺乳動物細胞性mRNAである、請求項32記載の二本鎖RNAのアナログ。
- mRNAがヒトmRNAである、請求項32記載の二本鎖RNAのアナログ。
- 末端3'ヒドロキシル基を含んでなる請求項32記載の二本鎖RNAのアナログ。
- 許容され得る担体および請求項32記載の二本鎖RNAのアナログを含む組成物。
- 二本鎖RNAの各々の鎖が21ヌクレオチド長である、請求項23または25記載の単離された二本鎖RNA。
- 二本鎖RNAの各々の鎖が22ヌクレオチド長である、請求項23または25記載の単離された二本鎖RNA。
- 二本鎖RNAの各々の鎖が23ヌクレオチド長である、請求項23または25記載の単離された二本鎖RNA。
- mRNAがヒトmRNAである、請求項27〜29いずれか記載の組成物。
- 二本鎖RNAの各々の鎖が21ヌクレオチド長である、請求項27〜29いずれか記載の組成物。
- 二本鎖RNAの各々の鎖が22ヌクレオチド長である、請求項27〜29いずれか記載の組成物。
- 二本鎖RNAの各々の鎖が23ヌクレオチド長である、請求項27〜29いずれか記載の組成物。
- 共有結合していない二本の別個のRNA鎖の形態である単離された二本鎖RNAであって、該単離された二本鎖RNAの各々の鎖は、21〜23ヌクレオチド長であり、該単離された二本鎖RNAの一方の鎖は、遺伝子のmRNAに対して完全な配列相補性を有し、該単離された二本鎖RNAは、mRNAの切断を引き起こすことによって遺伝子のmRNAのRNA干渉を媒介する、単離された二本鎖RNA。
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