JP6325974B2 - Rna干渉を媒介する短鎖rna分子 - Google Patents
Rna干渉を媒介する短鎖rna分子 Download PDFInfo
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Description
具体的には、本発明は、以下の特徴を有する。
〔1〕合成され単離された二本鎖RNA分子であって、該RNA分子は標的特異的な核酸改変が可能なものであり、該二本鎖RNA分子は第1および第2のRNA鎖を有し、該第1または第2のRNA鎖のいずれかが3’末端で改変またはブロッキングされており、それにより該RNA二本鎖分子の向かい合う3’末端でdsRNAプロセシングが開始される、上記RNA分子。
〔2〕一方の鎖が1〜5ヌクレオチドの3’突出部を有する、上記〔1〕に記載のRNA分子。
〔3〕標的特異的RNA干渉および/またはDNAメチル化が可能である、上記〔1〕に記載のRNA分子。
〔4〕3’突出部が1〜3ヌクレオチドである、上記〔2〕に記載のRNA分子。
〔5〕3’突出部が分解に対して安定化されている、上記〔2〕に記載のRNA分子。
〔6〕予め決定したmRNA標的分子に対して、少なくとも50%の同一性を有する配列を有する、上記〔1〕に記載のRNA分子。
〔7〕同一性が少なくとも70%である、上記〔6〕に記載のRNA分子。
〔8〕有効物質として上記〔1〕に記載の少なくとも1つの二本鎖RNA分子と、薬学的キャリアを含む、医薬組成物。
〔9〕診断用途のための、上記〔8〕に記載の組成物。
〔10〕治療用途のための、上記〔8〕に記載の組成物。
〔11〕第1および第2の鎖が19〜52塩基長である、上記〔1〕に記載の分子。
〔12〕第1または第2の鎖のいずれかが、該鎖の3’への17〜20ヌクレオチドの追加により改変またはブロッキングされている、上記〔11〕に記載の分子。
〔13〕細胞を上記〔1〕に記載の合成単離RNA二本鎖分子と接触させるステップを含む、細胞において標的遺伝子発現を低下させる方法。
〔14〕前記第1および第2のRNA鎖が同じ長さである、上記〔1〕に記載の分子。
〔15〕細胞を、各々が19〜52塩基長である2つの分離した鎖を有する上記〔1〕に記載の合成単離RNA二本鎖分子と接触させるステップを含む、細胞において標的mRNAレベルを低下させる方法であって、該合成単離RNA二本鎖分子は第1の鎖の3’末端で改変またはブロッキングされており、第2の鎖は連続した少なくとも19塩基対にわたって前記標的遺伝子mRNAと相補的である、上記方法。
〔16〕前記分離した鎖が同じ長さである、上記〔15〕に記載の方法。
〔17〕dsRNA前駆体のセンスもしくはアンチセンス鎖のいずれかの3’末端を改変またはブロッキングすることにより、該dsRNA前駆体の向かい合う3’末端から該分子のプロセシングを生じさせるステップを含む、dsRNA前駆体のプロセシングの方向性を選択する方法。
〔18〕dsRNAプロセシング反応系を、RNA前駆体の第1または第2の鎖のいずれかの3’末端で改変またはブロッキングされている52塩基対長までのRNA二本鎖と接触させるステップを含む、dsRNAプロセシングイベントにおいてRNA二本鎖から一本鎖切断産物を生成する方法。
〔19〕合成され単離された二本鎖siRNA分子であって、各々21塩基長の2本の鎖を有し、アンチセンス鎖の3’末端の最初の3ヌクレオチドのうち2つがGCであり、該siRNA分子は標的特異的な核酸改変が可能なものである、上記siRNA分子。
〔20〕平滑末端である、上記〔19〕に記載の単離された二本鎖siRNA。
〔21〕RNA鎖が化学的に合成される、上記〔19〕に記載のsiRNA分子。
〔22〕RNA鎖が酵素的に合成される、上記〔19〕に記載のsiRNA分子。
〔23〕少なくとも1つの修飾されたヌクレオチド類似体を含む、上記〔19〕に記載の単離された二本鎖siRNA分子。
〔24〕二本鎖siRNAが少なくとも1つの糖修飾リボヌクレオチドを含み、該糖修飾リボヌクレオチドの2’−OH基が、H、OR、R、ハロ、SH、SR、NH2、NHR、N(R)2またはCNから選択される基で置換され、Rは、C1−C6アルキル、アルケニルまたはアルキニルであり、ハロは、F、Cl、BrまたはIである、上記〔23〕に記載のsiRNA分子。
〔25〕二本鎖RNAが、ホスホロチオエート基を含む少なくとも1つの骨格修飾リボヌクレオチドを含む、上記〔19〕に記載のsiRNA分子。
〔26〕同一性が少なくとも70%である、上記〔19〕に記載の二本鎖siRNA分子。
〔27〕細胞抽出物中に存在する混入物を実質的に含まない、上記〔19〕に記載の二本鎖siRNA分子。
〔28〕下記のステップを含む、細胞または生物において標的特異的な核酸改変を媒介する方法:
(a)標的特異的な核酸改変が起こりうる条件下で、該細胞または生物を上記〔1〕に記載の二本鎖siRNA分子と接触させるステップ、および
(b)該二本鎖siRNAに実質的に対応する配列部分を有する標的核酸に対する、該二本鎖siRNAにより引き起こされる標的特異的な核酸改変を媒介するステップ。
〔29〕核酸改変がRNA干渉および/またはDNAメチル化である、上記〔28〕に記載の方法。
〔30〕接触ステップが、二本鎖siRNA分子を標的細胞に導入し、そこで標的特異的な核酸改変を起こさせうるステップを含む、上記〔28〕に記載の方法。
〔31〕導入ステップが、キャリア媒介送達または注入を含む、上記〔30〕に記載の方法。
〔32〕上記〔19〕に記載の少なくとも1つの二本鎖siRNA分子とキャリアを含む、組成物。
〔33〕キャリアが診断用途に適したものである、上記〔32〕に記載の組成物。
〔34〕キャリアが治療用途に適したものである、上記〔32〕に記載の組成物。
〔35〕アンチセンス鎖およびセンス鎖を有する合成され単離された二本鎖siRNA分子であって、各鎖が21塩基長であり、該siRNA分子は19塩基対の相補的な中央領域を有し、該siRNA分子は各末端に3’ヌクレオチド突出部を有し、アンチセンス鎖の3’末端の最初の5ヌクレオチドのうち2つがGUである、上記siRNA分子。
〔36〕RNA鎖が化学的に合成される、上記〔35〕に記載のsiRNA分子。
〔37〕RNA鎖が酵素的に合成される、上記〔35〕に記載のsiRNA分子。
〔38〕少なくとも1つの修飾されたヌクレオチド類似体を含む、上記〔35〕に記載の単離された二本鎖siRNA分子。
〔39〕二本鎖siRNAが少なくとも1つの糖修飾リボヌクレオチドを含み、該糖修飾リボヌクレオチドの2’−OH基が、H、OR、R、ハロ、SH、SR、NH2、NHR、N(R)2またはCNから選択される基で置換され、Rは、C1−C6アルキル、アルケニルまたはアルキニルであり、ハロは、F、Cl、BrまたはIである、上記〔38〕に記載のsiRNA分子。
〔40〕二本鎖RNAが、ホスホロチオエート基を含む少なくとも1つの骨格修飾リボヌクレオチドを含む、上記〔35〕に記載のsiRNA分子。
〔41〕細胞抽出物中に存在する混入物を実質的に含まない、上記〔1〕に記載のsiRNA分子。
〔42〕下記のステップを含む、細胞または生物において標的特異的な核酸改変を媒介する方法:
(a)標的特異的な核酸改変が起こりうる条件下で、該細胞または生物を上記〔35〕に記載の二本鎖siRNA分子と接触させるステップ、および
(b)該二本鎖RNAに実質的に対応する配列部分を有する標的核酸に対する、該二本鎖RNAにより引き起こされる標的特異的な核酸改変を媒介するステップ。
〔43〕核酸改変がRNA干渉および/またはDNAメチル化である、上記〔42〕に記載の方法。
〔44〕接触ステップが、二本鎖RNA分子を標的細胞に導入し、そこで標的特異的な核酸改変を起こさせうるステップを含む、上記〔42〕に記載の方法。
〔45〕導入ステップが、キャリア媒介送達または注入を含む、上記〔44〕に記載の方法。
〔46〕上記〔35〕に記載の少なくとも1つの二本鎖siRNA分子とキャリアを含む、組成物。
〔47〕キャリアが診断用途に適したものである、上記〔46〕に記載の組成物。
〔48〕キャリアが治療用途に適したものである、上記〔46〕に記載の組成物。
(a)各々が19〜25塩基長、例えば19〜23塩基長を有する2本のRNA鎖を合成するステップであって、このRNA鎖は二本鎖RNA分子を形成することができるものであり、好ましくは少なくとも1本が1〜5塩基の3’突出部を有する、上記ステップ、
(b)二本鎖RNA分子が形成される条件下で合成RNA鎖を結合させるステップであって、得られる二本鎖RNA分子は標的特異的な核酸改変、特にRNA干渉および/またはDNAメチル化を媒介することが可能なものである、上記ステップ。
(a)標的特異的な核酸改変が起こりうる条件下で、上記細胞または生物を本発明の二本鎖RNA分子と接触させるステップ、
(b)上記二本鎖RNAと実質的に対応する配列部分を有する標的核酸に対する、上記二本鎖RNAにより引き起こされる標的特異的な核酸改変を媒介するステップ。
(i)標的遺伝子阻害を含まない対照細胞または対照生物、
(ii)標的遺伝子阻害を含む細胞または生物、および
(iii)標的遺伝子阻害と、外因性標的核酸による標的遺伝子の相補を含む細胞または生物。
(a)上記標的タンパク質をコードする少なくとも1つの内因性標的遺伝子を発現することができる、真核細胞またはヒト以外の真核生物、
(b)上記少なくとも1つの内因性標的遺伝子の発現を阻害することができる、少なくとも1つの二本鎖RNA分子、および
(c)薬理学的特性を同定および/または特性決定しようとする、試験物質または試験物質のコレクション。
(d)上記標的タンパク質または該標的タンパク質の変異体もしくは突然変異形態をコードする少なくとも1つの外因性標的核酸であって、この外因性標的核酸は、二本鎖RNA分子による発現の阻害が、上記内因性標的遺伝子の発現より実質的に低いという点で、該内因性標的遺伝子とは核酸レベルで異なるものである、上記外因性標的核酸。
図1:38bpという短い二本鎖RNAは、RNAiを媒介することができる。
RNAiは、主として21および22塩基の短鎖干渉RNA(siRNA)を生成するdsRNA(センス鎖は黒、アンチセンス鎖は赤)のプロセシングで開始すると推定される。短い3’突出塩基が、dsRNA上に存在すれば、これは、短鎖dsRNAのプロセシングに有益であると考えられる。これから特性決定しようとするdsRNAプロセシングタンパク質は、緑色および青色の長円形として表し、非対称にdsRNA上に集合させる。本発明のモデルでは、これは、推定上の青色タンパク質またはタンパク質ドメインと、3’から5’方向のsiRNA鎖との結合により説明されるのに対し、推定上の緑色タンパク質またはタンパク質ドメインは、向き合うsiRNA鎖と必ず結合する。これらのタンパク質またはサブセットは、siRNA二本鎖と会合したままであり、dsRNAプロセシング反応の方向により決定される配向を保存している。青色タンパク質と会合したsiRNA配列だけが標的RNA切断を指示することができる。エンドヌクレアーゼ複合体は、短い干渉リボ核タンパク質複合体またはsiRNPと呼ばれる。本発明では、dsRNAを切断するエンドヌクレアーゼは、恐らく、標的認識に使用されない受動siRNAを一時的に置換することにより、標的RNAも切断することができると推定する。次に、この標的RNAは、配列相補的ガイドsiRNAにより認識される領域の中心部で切断される。
(A)実験戦略の概要。キャップを有し、かつポリアデニル化されたセンス標的mRNAを描くと共に、センスおよびアンチセンスsiRNAの相対位置を示す。8つの異なるアンチセンス鎖に従って8系統の二本鎖を用意した。siRNA配列と、突出ヌクレオチドの数を1塩基ずつ変化させた。
(A)32P(星印)キャップ標識センスおよびアンチセンス標的RNAと、siRNA二本鎖をグラフで示した図。センスおよびアンチセンス標的RNA切断の位置は、siRNA二本鎖の上方および下方に、それぞれ三角形で示す。
2塩基3’突出部(灰色のNN)は、表示したように配列および組成を改変した(T、2’−デオキシチミジン、dG、2’−デオキシグアノシン;星印、野生型siRNA二本鎖)。正規化した干渉比は、図11で記載したように決定した。野生型配列は図14に示したものと同じである。
1.1.実験手順
1.1.1 in vitro RNAi
以前記載されている(Tuschlら、1999;Zamoreら、2000)ように、in vitro RNAiおよび溶解物調製を実施した。最適なATP再生のためには、新しく溶解したクレアチンキナーゼ(Roche)を用いる必要がある。RNAi翻訳アッセイ(図1)は、5nMのdsRNA濃度と、25℃で15分の長いプレインキュベーション時間で実施した後、in vitro転写、キャッピングおよびポリアデニル化したPp−lucおよびRr−lucリポーターmRNAを添加した。インキュベーションを1時間継続した後、二重ルシフェラーゼアッセイ(Promega)およびモノライト3010Cルミノメーター(PharMingen)を用いて、Pp−lucおよびRr−lucタンパク質の相対量を分析した。
標準的手順を用いて、T7またはSP6プロモーター配列を有するPCR鋳型からのRNAのin vitro転写を実施した(例えば、Tuschlら、1998を参照)。Expedite RNAホスホルアミダイト(Proligo)を用いて、合成RNAを調製した。ジメトキシトリチル−1,4−ベンゼンジメタノール−スクシニル−アミノプロピル−CPGを用いて、3’アダプターオリゴヌクレオチドを合成した。オリゴリボヌクレオチドを、3mlの32%アンモニア/エタノール(3/1)において、55℃で4時間(Expedite RNA)または55℃で16時間かけて脱保護した(3’および5’アダプターDNA/RNAキメラオリゴヌクレオチド)後、以前記載されている(Tuschlら、1993)ように、脱シリル化してからゲル精製した。長い3’突出部を含むdsRNAを調製するためのRNA転写物は、センス方向にT7プロモーターを、アンチセンス方向にSP6プロモーターを含むPCR鋳型から作製した。5’プライマーとしてGCGTAATACGACTCACTATAGAACAATTGCTTTTACAG(下線部、T7プロモーター)と、3’プライマーとしてATTTAGGTGACACTATAGGCATAAAGAATTGAAGA(下線部、SP6プロモーター)、ならびに、鋳型として線状化Pp−lucプラスミド(pGEM−luc配列)(Tuschlら、1999)を用いて、センスおよびアンチセンス標的RNA用の転写鋳型をPCR増幅した。T7転写センスRNAは、177塩基長であり、開始コドンに対して位置113〜273のPp−luc配列と、これに続いて、3’末端にSP6プロモーター配列の17塩基の相補配列(complement)を含む。平滑末端dsRNA形成用の転写物は、単一のプロモーター配列だけを含む2つの異なるPCR産物からの転写によって調製した。
10nM dsRNAを15分プレインキュベートした後、10nMキャップ標識標的RNAをを添加することにより、標準RNAi反応を実施した。プロテイナーゼK処理(Tuschlら、1999)により、さらに2時間(図2A)または2.5時間(図5Bおよび6B)インキュベートした後、反応を停止した。次に、8または10%配列決定用ゲル上でサンプルを分析した。21および22塩基の合成RNA二本鎖を100nM最終濃度で用いた(図5B)。
標的RNAの不在下で、ショウジョウバエ溶解物における放射性標識dsRNAのインキュベーションにより(200μl反応物、1時間インキュベーション、50nM dsP111、または100nM dsP52もしくはdsP39)、21塩基のRNAを生成した。次に、反応混合物をプロテイナーゼKで処理した(Tuschlら、1999)後、dsRNAプロセシング産物を変性15%ポリアクリルアミドゲル上で分離した。少なくとも18〜24塩基のサイズ範囲を含むバンドを除去し、0.3M NaClに4℃で一晩かけて溶離した後、シリコン処理管に導入した。エタノール沈降によりRNAを回収した後、脱リン酸化した(30μl反応物、30分、50℃、10Uアルカリホスファターゼ、Roche)。フェノール/クロロホルム抽出により反応を停止し、RNAをエタノール沈降させた。次に、3’アダプターオリゴヌクレオチド(pUUUaaccgcatccttctcx:大文字はRNA;小文字はDNA;pはリン酸;xは4−ヒドロキシメチルベンジル)を脱リン酸化した約21塩基のRNAと連結させた(20μl反応物、30分、37℃、5μM 3’アダプター、50mM Tris−HCl、pH7.6、10mM MgCl2、0.2mM ATP、0.1mg/mlアセチル化BSA、15%DMSO、25U T4 RNAリガーゼ、Amersham-Pharmacia)(PanおよびUhlenbeck, 1992)。等量の8M尿素/50mM EDTA停止混合物(stopmix)の添加により連結反応を停止した後、15%ゲルに直接ロードした。連結収率は50%を超えた。連結産物をゲルから回収した後、5’−リン酸化した(20μl反応物、30分、37℃、2mM ATP、5U T4ポリヌクレオチドキナーゼ、NEB)。フェノール/クロロホルム抽出によりリン酸化反応を停止した後、エタノール沈降によりRNAを回収した。次に、前記と同様に、5’アダプター(tactaatacgactcactAAA:大文字はRNA;小文字はDNA)をリン酸化連結産物と連結させた。新しい連結産物をゲル精製し、キャリアとして用いる逆転写プライマー(GACTAGCTGGAATTCAAGGATGCGGTTAAA:太字はEcoRI部位)の存在下で、ゲル切片から溶離させた。逆転写(15μl反応物、30分、42℃、150U SuperscriptII逆転写酵素、Life Technologies)の後、5’プライマーCAGCCAACGGAATTCATACGACTCACTAAA(太字はEcoRI部位)と、3’RTプライマーを用いたPCRを実施した。PCR産物をフェノール/クロロホルム抽出により精製した後、エタノール沈降させた。次に、PCR産物をEcoRI(NEB)で消化してから、T4 DNAリガーゼ(高濃度、NEB)を用いてコンカテマー化する。サイズが200〜800bpの範囲にあるコンカテマーを低融点アガロースゲル上で分離し、標準的な融解およびフェノール抽出手順によりゲルから回収した後、エタノール沈降させた。非対合末端を標準的条件下でTaqポリメラーゼと一緒に72℃で15分インキュベートすることにより充填した後、TOPO TAクローニングキット(Invitrogen)を用いて、DNA産物をpCR2.1−TOPOベクターに直接連結した。PCRと、M13−20およびM13逆方向配列決定用プライマーを用いて、コロニーをスクリーニングした。カスタム(custom)配列決定(Sequence Laboratories Gottingen GmbH, ドイツ)のためにPCR産物を直接提出した。平均して、1クローン当たり4〜5個の21mer配列が得られた。
放射性標識し、ゲル精製したsiRNAおよび2D−TLCのヌクレアーゼP1消化を記載されている通りに実施した(Zamoreら、2000)。2μg/μlキャリアtRNAと30UリボヌクレアーゼT2(Life Technologies)を用いて、10mM酢酸アンモニウム(pH4.5)中、10μl反応物において、ヌクレアーゼT2消化を50℃で3時間実施した。非放射性標準の泳動をUVシャドウイング(shadowing)により測定した。ヌクレオシド−3’,5’−二リン酸の同一性は、γ−32P−ATPおよびT4ポリヌクレオチドキナーゼを用いた市販のヌクレオシド3’−一リン酸の5’−32Pリン酸化により調製した標準によるT2消化産物の同時泳動によって確認した(データは示していない)。
1.2.1 21および22塩基のRNA断片のプロセシングに必要な長さ
キイロショウジョウバエ合胞体胚から調製した溶解物は、in vitroにおいてRNAiを再現することから、RNAi機構の生化学的分析の新たなツールを提供するものである(Tuschlら、1999;Zamoreら、2000)。RNAiのためのdsRNAに必要な長さについてのin vitroおよびin vivo分析から、標的mRNAを分解する上で、短いdsRNA(<150bp)は、長いdsRNAより効果が低いことが明らかにされている(Caplenら、2000;Hammondら、2000;Ngoら、1998);Tuschlら、1999)。このmRNA分解効率が低い理由はわかっていない。従って、本発明者は、ショウジョウバエ溶解物における最適化条件下で(Zomoreら、2000)、標的RNA分解のためのdsRNAに必要な正確な長さを調べた。数系統のdsRNAを合成し、ホタルルシフェラーゼ(Pp−luc)リポーターRNAに対して指令させた。標的RNA発現の特異的抑制を二重ルシフェラーゼアッセイ(Tuschlら、1999)によりモニタリングした(図1Aおよび1B)。本発明者は、38bpという短いdsRNAの標的RNA発現の特異的阻害を検出したが、29〜36bpのdsRNAはこの過程において有効ではなかった。効果は、Pp−luc mRNAの標的位置および阻害度とは無関係で、dsRNAの長さと相関していた。すなわち、長鎖dsRNAの方が、短鎖dsRNAより有効であった。
ショウジョウバエ溶解物にdsRNAおよび5’−キャップ標識RNAを添加すると、標的RNAの配列特異的分解が起こる(Tuschlら、1999)。標的mRNAは、dsRNAと同一性のある領域内でしか切断されず、標的切断部位の多くは、21〜23塩基ずつ分離された(Zamoreら、2000)。従って、所与のdsRNAの切断部位の数は、dsRNAの長さを21で割った数とおおまかに対応することが予想された。本発明者は、キャップにおいて5’放射性標識されたセンスおよびアンチセンス標的RNA上の標的切断部位をマッピングした(Zamoreら、2000)(図3Aおよび3B)。配列決定用ゲル上で安定した5’切断産物を分離し、標的RNAからの部分的RNaseT1およびアルカリ性加水分解標準(ladder)との比較により、切断位置を決定した。
21〜23塩基のRNA断片を特性決定するために、RNA断片の5’および3’末端を調べた。ゲル精製した21〜23塩基のRNAを過ヨウ素酸化した後、β脱離すると、末端2’および3’ヒドロキシル基の存在が示された。21〜23merはまた、アルカリ性ホスファターゼ処理に応答性であり、これは5’末端リン酸基の存在を意味する。5’リン酸および3’ヒドロキシル末端の存在は、dsRNAが大腸菌RNaseIIIと類似した酵素活性によりプロセシングされ得ることを示唆している(確認のため、(Dunn, 1982;Nicholson, 1999;Robertson, 1990:Robertson, 1982)を参照)。
dsRNAプロセシングの産物の分析から、RNaseIII切断反応のあらゆる特徴を有する反応によって約21断片が生成されることがわかった(Dunn, 1982;Nicholson, 1999;Robertson, 1990;Robertson, 1982)。RNaseIIIは、dsRNAの両鎖に2つの付着切断を形成し、約2塩基の3’突出部を残す。本発明者は、クローン化した約21塩基断片のいくつかと配列が同じである21および22塩基のRNAを化学的に合成し、標的RNA分解を媒介する能力についてそれらを試験した(図5Aおよび5B)。21および22塩基のRNA二本鎖を、溶解物中100nMの濃度(52bpの対照dsRNAの10倍の濃度)でインキュベートした。これらの条件下で、標的RNA切断は容易に検出可能である。21および22塩基二本鎖の濃度を100から10nMまで下げても、やはり標的RNA切断が起こる。しかし、二本鎖の濃度を100から1,000nMに高めても、標的切断は増加しない。これは恐らく、溶解物内の制限タンパク質因子によるものであろう。
本発明者は、短い平滑末端dsRNAが、dsRNAの末端からプロセシングされることを明らかにした。RNAiにおけるdsRNAの長さ依存の研究中に、本発明者が、17〜20塩基の突出3’末端を有するdsRNAも分析したところ、驚くべきことに、これらが、平滑末端dsRNAより効力が弱いことがわかった。長い3’末端の阻害効果は、100bpまでのdsRNAに特に顕著であったが、これより長いdsRNAについてはそれほど強くなかった。未改変ゲル分析(データは示していない)によれば、この効果は、不完全なdsRNA形成によるものではなかった。本発明者は、長い突出3’末端の阻害効果を、短いRNA二本鎖の2つの末端の一方だけに対するdsRNAプロセシングを指令するツールとして使用できるかどうかを試験した。
新しい生化学データを用いて、どのようにしてdsRNAがmRNAをターゲッティングし、破壊するかについてのモデルを更新する(図7)。二本鎖RNAはまず、主に21および22塩基長で、かつ、RNaseIII様反応と類似した付着3’末端を有する短いRNA二本鎖にプロセシングされる(Dunn, 1982;Nicholson, 1999;Robertson, 1982)。プロセシングされたRNA断片の21〜23塩基長に基づき、RNaseIII様活性がRNAiに関与し得ることがすでに想定されていた(Bass, 2000)。この仮定は、RNaseIII反応産物に観察されるように、siRNAの末端に5’リン酸および3’ヒドロキシルが存在することにより支持される(Dunn, 1982;Nicholson, 1999)。細菌RNaseIII、S.セレビシエにおける真核生物相同体Rnt1p、およびS.ポンベにおけるPac1pは、リボソームRNA、ならびに、snRNAおよびsnoRNAのプロセシングにおいて機能することがわかっている(例えば、Chanfreauら、2000参照)。
2.1 方法
2.1.1 RNA調製
Expedite RNAホスホルアミダイトとチミジンホスホルアミダイト(Proligo, Germany)を用いて、21塩基のRNAを化学的に合成した。合成オリゴヌクレオチドを脱保護してからゲル精製した(実施例1)後、Sep−Pak C18カートリッジ(Waters, Milford, MA, USA)により精製を実施した(Tuschl, 1993)。siRNA配列がターゲッティングするGL2(アクセッション番号X65324)とGL3ルシフェラーゼ(アクセッション番号U47296)は、開始コドンの第1ヌクレオチドに対してコード領域153〜173と対応し、siRNAがターゲッティングするRL(アクセッション番号AF025846)は、開始コドン後の領域119〜129と対応した。より長いRNAは、PCR産物からT7RNAポリメラーゼで転写した後、ゲルおよびSep−Pak精製に付した。49および484bpのGL2またはGL3dsRNAは、翻訳の開始に対して、位置113〜161および113〜596にそれぞれ対応した。50および501bpのRL dsRNAは、位置118〜167および118〜618にそれぞれ対応した。ヒト化GFP(hG)をターゲッティングするdsRNA合成のためのPCR鋳型をpAD3から増幅した(Kehlenbach, 1998)ところ、50および501bpのhG dsRNAは、翻訳の開始に対して、位置118〜167および118〜618にそれぞれ対応した。
10%FBS、100単位/mlペニシリンおよび100μg/mlストレプトマイシンを補充したシュナイダーのショウジョウバエ培地(Life Technologies)において25℃で、S2細胞を増殖させた。10%FBS、100単位/mlペニシリンおよび100μg/mlストレプトマイシンを補充したダルベッコの改変イーグル培地において37℃で、293、NIH/3T3、HeLaS3、COS−7細胞を増殖させた。細胞を定期的に継代させて、対数増殖を維持した。約80%密集度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てから、抗生物質を含まない新鮮な培地で5倍に希釈した(1〜3×105細胞/ml)後、24ウェルプレート(500μl/ウェル)に移した。S2細胞はトリプシン処理せずに開裂反応に付した。付着細胞系について製造者が記載しているように、リポフェクトアミン2000試薬(Life Technologies)を用いて、トランスフェクションを実施した。1ウェルにつき、リポソームに組み込まれた1.0μgのpGL2−Control(Promega)またはpGL3−Control(Promega)、0.1μgのpRL−TK(Promega)および0.28μgのsiRNA二本鎖またはdsRNAを導入した;最終量は、1ウェル当たり600μlであった。トランスフェクションの後、細胞を20時間インキュベートしたが、その後の細胞は健常のようであった。次に、二重ルシフェラーゼアッセイ(Promega)で、ルシフェラーゼ発現をモニタリングした。1.1μgのhGFPコード化pAD3と0.28μgのinvGL2 inGL2 siRNAの共トランスフェクション後、哺乳動物細胞系の蛍光顕微鏡検査により、トランスフェクション効率を測定したところ、70〜90%であった。リポータープラスミドをXL−1 Blue(Stratagene)において増幅した後、Qiagenエンドフリー・マキシ・プラスミドキット(Qiagen EndoFree Maxi Plasmid Kit)を用いて精製した。
siRNAが、組織培養物においてもRNAiを媒介することができるか否かを試験するために、本発明者は、ウミシイタケ(Renilla reniformis)および、ホタルルシフェラーゼ(Photinus pyralis、GL2およびGL3)の2つの配列種をコードするリポーター遺伝子に対して指令される対称2塩基3’突出部を有する21塩基siRNA二本鎖を合成した(図8a、b)。カチオンリポソームを用いて、siRNA二本鎖をリポータープラスミドの組合せpGL2/pRLまたはpGL3/pRLと一緒に、キイロショウジョウバエ・シュナイダーS2細胞または哺乳動物細胞に共トランスフェクトした。トランスフェクションから20時間後にルシフェラーゼ活性を測定した。試験したすべての細胞系において、本発明者は、相同siRNA二本鎖(cognate siRNA duplex)の存在下でリポーター遺伝子の発現の特異的減弱を観察した(図9a〜j)。驚くことに、絶対ルシフェラーゼ発現レベルは、非相同siRNAによる影響を受けなかった。これは、21塩基のRNA二本鎖(例えば、HeLa細胞については図10a〜d)による有害な副作用がないことを意味している。キイロショウジョウバエS2細胞(図9a、b)において、ルシフェラーゼの特異的阻害は完全であった。リポーター遺伝子が50〜100倍強く発現した哺乳動物細胞では、特異的抑制は完全ではなかった(図9c〜j)。相同siRNAに応答して、GL2発現は、3〜12倍、GL3発現は9〜25倍、またRL発現は1〜3倍減弱した。293細胞については、RL siRNAによるRLルシフェラーゼのターゲッティングは無効であったが、GL2およびGL3標的は、特異的に応答した(図9i、j)。293細胞でRL発現の減弱がないのは、この発現が、試験した他の哺乳動物細胞系と比べて5〜20倍高いこと、および/またはRNA二次構造もしくは会合タンパク質のために標的配列の受容能力が制限されたことによるものであろう。それでも、相同siRNA二本鎖によるGL2およびGL3ルシフェラーゼの特異的ターゲッティングは、RNAiが293細胞においても機能していることを示している。
3.1 材料と方法
3.1.1 RNA調製とRNAiアッセイ
実施例1または2、あるいは、これまでの文献(Tuschlら、1999;Zamoreら、2000)に記載されているように、化学的RNA合成、アニーリング、およびルシフェラーゼに基づくRNAiアッセイを実施した。すべてのsiRNA二本鎖はホタルルシフェラーゼに対して指令され、ルシフェラーゼmRNA配列は、記載されている(Tuschlら、1999)ように、pGEM−luc(GenBankアクセッション番号X65316)由来のものであった。キイロショウジョウバエRNAi/翻訳反応において、siRNA二本鎖を15分インキュベートしてから、mRNAを添加した。翻訳に基づくRNAiアッセイを少なくとも3回繰り返して実施した。
3.2.1 21塩基のsiRNAの二本鎖における3’突出部の変動
前述のように、siRNA二本鎖の3’末端で2または3非対合ヌクレオチドは、それぞれの平滑末端二本鎖と比べて、標的RNA分解が効率的である。末端ヌクレオチドの機能のさらに総合的分析を実施するために、本発明者は、5つの21塩基センスsiRNA(各々、標的RNAに対する1塩基で表される)と、8つの21塩基アンチセンスsiRNA(各々、標的に対する1塩基で表される)を合成した(図11A)。センスおよびアンチセンスsiRNAを組み合わせることにより、7塩基3’突出部〜4塩基5’突出部の範囲にある合成突出末端を有する8系統のsiRNA二本鎖を作製した。二重ルシフェラーゼアッセイ系(Tuschlら、1999;Zamoreら、2000)を用いて、siRNA二本鎖の干渉を測定した。siRNA二本鎖は、ホタルルシフェラーゼmRNAに対して指令され、ウミシイタケルシフェラーゼmRNAを内部対照として用いた。siRNA二本鎖の存在下で、標的と対照ルシフェラーゼ活性のルミネセンス比を測定した後、dsRNAの不在下で得られた比に対して正規化した。比較のため、長いdsRNA(39〜504bp)の干渉比を図11Bに示す。長鎖dsRNA(図11A)については5nM、また、siRNA二本鎖(図11C〜J)については100nMの濃度で、干渉比を測定した。5nMの504bp dsRNAの完全なプロセシングにより、120nMの全siRNA二本鎖が得られたことから、siRNAについては100nM濃度を選択した。
RNAiに対するsiRNAの長さの影響を調べるために、本発明者は、3つの21塩基アンチセンス鎖と8つの18〜25塩基センス鎖とを組み合わせて、3系統のsiRNA二本鎖を作製した。アンチセンスsiRNAの3’突出部は、各siRNA二本鎖系統における1、2または3塩基に固定したのに対し、センスsiRNAは、その3’末端で変動させた(図12A)。センスsiRNAの長さとは無関係に、アンチセンスsiRNAの2塩基の3’突出部を有する二本鎖(図12C)は、1または3塩基の3’突出部を有するもの(図12B、D)より活性が高いことがわかった。アンチセンスsiRNAの1塩基の3’突出部を有する第1の系統では、センスsiRNAの1および2塩基の3’突出部をそれぞれ有する、21および22塩基センスsiRNAの二本鎖の活性が最も高かった。19〜25塩基のセンスsiRNAを有する二本鎖もRNAを媒介することができたが、程度は低かった。同様に、アンチセンスsiRNAの2塩基突出部を有する第2系統では、2塩基の3’突出部を有する21塩基のsiRNA二本鎖の活性が最も高く、18〜25塩基のセンスsiRNAとのその他すべての組合せは、有意な程度まで活性であった。3塩基のアンチセンスsiRNA3’突出部を有する最後の系統では、20塩基のセンスsiRNAおよび2塩基のセンス3’突出部を有する二本鎖だけが標的RNA発現を減弱することができた。以上、これらの結果から、siRNAの長さと共に、3’突出部の長さが重要であることと、2塩基3’突出部を有する21塩基のsiRNAの二本鎖がRNAiには最適であることがわかる。
次に、本発明者は、対称の2塩基3’突出部を維持しながら、両siRNA鎖の長さを同時に変化させて生じる影響を調べた(図13A)。図11Hの21塩基のsiRNA二本鎖を基準として含む2系統のsiRNA二本鎖を作製した。センスsiRNA(図13B)の3’末端またはアンチセンスsiRNA(図13C)の3’末端で塩基対合部分を延長することにより、二本鎖の長さを20〜25bpで変動させた。20〜23bpの二本鎖は、標的ルシフェラーゼ活性の特異的抑制を起こしたが、21塩基のsiRNA二本鎖は、他の二本鎖のどちらと比較しても少なくとも8倍有効であった。24および25塩基のsiRNA二本鎖は、検出可能な干渉を全く起こさなかった。配列特異的効果は、二本鎖の両末端における変動が同様の効果を生じたため、わずかであった。
RNAiにおけるsiRNAリボース残基の重要性を評価するため、2’−デオキシまたは2’−O−メチル修飾鎖を含む21塩基のsiRNAおよび2塩基3’突出部を有する二本鎖を試験した(図14)。2’−デオキシヌクレオチドによる2塩基3’突出部の置換では影響がなく、対合領域における突出部と隣接した2つの別のリボヌクレオチドの置換でも、有意に活性のsiRNAが生じた。従って、siRNA二本鎖の42塩基のうち8つをDNA残基で置換しても、活性は失われなかった。2’−デオキシ残基による一方または両方のsiRNA鎖の完全な置換では、2’−O−メチル残基による置換と同様に、RNAiを破壊した。
22塩基のsiRNA二本鎖および21塩基/22塩基の二本鎖について、標的RNA切断位置を事前に決定した。標的RNA切断の位置は、siRNA二本鎖が占める領域の中心部、すなわち、21または22塩基のsiRNAガイド配列と相補的な第1塩基から11または12塩基下流に位置することがわかった。2塩基3’突出部を有する5つの別個の21塩基siRNA二本鎖(図15A)を5’キャップ標識センスまたはアンチセンス標的RNAと一緒にキイロショウジョウバエ溶解物中でインキュベートした(Tuschlら、1999;Zamoreら、2000)。5’切断産物を配列決定用ゲル上で分離した(図15B)。切断されたセンス標的RNAの量は、翻訳に基づくアッセイで決定されるsiRNA二本鎖の効率と相関しており、siRNA二本鎖1、2および4(図15Bおよび11H、G、E)は、二本鎖3および5(図15Bおよび11F、D)より速く標的RNAを切断する。注目すべきことに、5’切断産物および投入標的RNAの放射活性の合計は、時間に関して一定ではなく、5’切断産物は蓄積しなかった。恐らく、5’−キャップのポリ(A)テイルのいずれかが欠如しているために、siRNA−エンドヌクレアーゼ複合体から放出した切断産物は急速に分解されるのであろう。
2塩基の3’突出部が、siRNA機能には好ましい。本発明者は、突出塩基の配列が、標的認識に寄与するのか、またはこの配列が、エンドヌクレアーゼ複合体(RISCまたはsiRNP)の認識に必要な特徴であるだけなのかを知ろうとした。本発明者は、AA、CC、GG、UUおよびUG3’突出部を有するセンスおよびアンチセンスsiRNAを合成し、2’−デオキシ修飾TdGおよびTTを含有させた。野生型siRNAは、センス3’突出部にAAを、また、アンチセンス3’突出部にUGを含んでいた(AA/UG)。siRNA二本鎖はすべて、干渉アッセイにおいて機能的であり、標的発現を少なくとも5倍減弱した(図17)。10倍以上標的発現を減弱した最も効率的なsiRNA二本鎖は、配列型:NN/UG、NN/UU、NN/TdG、およびNN/TT(Nは任意のヌクレオチドである)のものであった。AA、CCまたはGGのアンチセンスsiRNA3’突出部を有するsiRNA二本鎖は、野生型配列UGまたは突然変異配列UUと比較して、2〜4倍活性が低かった。RNAi効率が低いのは、恐らく、末端から2番目の3’塩基が配列特異的標識認識に寄与するためと考えられる。というのは、3’末端塩基は、GからUに改変しても、影響がないからである。
標的認識の配列特異性を調べるため、本発明者は、siRNA二本鎖の対合部分に配列改変を導入し、サイレンシングの効率を調べた。配列改変は、3または4塩基長の短い部分を逆転させるか、あるいは、点突然変異として導入した(図18)。一方のsiRNA鎖の配列改変は、相補的siRNA鎖において補償され、これによって、塩基対合したsiRNA二本鎖構造の不安定化(pertubing)を回避した。合成にかかるコストを下げるため、2塩基の3’突出部の配列は、すべてTT(T、2’−デオキシチミジン)とした。TT/TT基準siRNA二本鎖は、RNAiについて、野生型siRNA二本鎖AA/UGと同等であった(図17)。リポーターmRNA破壊を媒介する能力は、翻訳に基づくルミネセンスアッセイを用いて定量化した。逆転配列部分有するsiRNAの二本鎖は、ホタルルシフェラーゼリポーターをターゲッティングする能力が著しく低いことがわかった(図18)。アンチセンスsiRNAの3’末端と中央部との間に位置する配列改変は、標的RNA認識を完全に破壊したが、アンチセンスsiRNAの5’末端付近の突然変異は、わずかな程度のサイレンシングを呈示する。推定標的RNA切断部位の反対側に直接、または推定部位から1塩基離れて位置するA/U塩基対のトランスバージョンによって、標的RNA切断が阻止されるが、これは、siRNA二本鎖の中心部内の単一突然変異が、ミスマッチ標的を識別することを示している。
siRNAは、昆虫細胞だけではなく、哺乳動物細胞においても、遺伝子発現を不活性化するための有用な試薬であり、治療用途に極めて有望である。本発明者は、キイロショウジョウバエ胚溶解物において効率的な標的RNA分解を促進するのに必要なsiRNA二本鎖の構造上の決定因子を系統的に分析することにより、最も効力のあるsiRNA二本鎖の設計についての法則を提供した。完全なsiRNA二本鎖は、全RNAの同等量を用いれば、500bpのdsRNAと同等の効率で、遺伝子発現をサイレンシングすることができる。
効率的なサイレンシングsiRNA二本鎖は、21塩基のアンチセンスsiRNAから構成されるため、2塩基3’突出末端を有する19bp二重らせんを形成するように選択しなければならない。2塩基3’突出リボヌクレオチドの2’−デオキシ置換は、RNAiに影響を及ぼさないが、RNA合成にかかるコスト削減に役立ち、siRNA二本鎖のRNase抵抗を増強することができる。ところが、これより広範囲な2’−デオキシまたは2’−O−メチル修飾は、恐らく、siRNAP集合のためのタンパク質会合を妨害するために、siRNAがRNAiを媒介する能力を低下させる。
Claims (1)
- アンチセンス鎖およびセンス鎖を有し、かつ、標的特異的RNA干渉活性を有する合成され単離された二本鎖RNA分子であって、各鎖が21〜25ヌクレオチドからなる同一の塩基長であり、該RNA分子は19〜23塩基対の相補的な中央領域を有し、該RNA分子は各末端に2ヌクレオチドの3'突出部を有し、ならびに、該アンチセンス鎖の3'末端の最初の5ヌクレオチドのうち連続する2つのヌクレオチド(5'−3')がUGである、上記RNA分子。
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