JP2006501808A - 増強された効力を有するオリゴヌクレオチド組成物 - Google Patents
増強された効力を有するオリゴヌクレオチド組成物 Download PDFInfo
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Abstract
Description
アンチセンスおよび二本鎖RNAオリゴヌクレオチドは有望な治療剤であり,遺伝子機能を解明するための有用な研究ツールである。しかし,そのような組成物を用いて蛋白質合成の効率的な阻害を達成することはしばしば困難である。その治療上の活性を最大限にするために,従来技術のアンチセンスおよび二本鎖RNAオリゴヌクレオチドが蛋白質合成を阻害する効率を増強することによりこれらを改良することは大きな利点があるであろう。
本発明は,少なくとも部分的には,改良された遺伝子発現阻害を与えるアンチセンスおよび二本鎖オリゴヌクレオチド組成物の発見に基づく。特に,本発明のオリゴヌクレオチド組成物は,アンチセンスまたは二本鎖オリゴヌクレオチドの組み合わせを使用する。
従来のある種のアンチセンスおよび二本鎖RNAオリゴヌクレオチドを用いて蛋白質合成を阻害することは可能であったが,有効なオリゴヌクレオチドを同定するためには多数回のトランスフェクションが必要であった。本発明は,とりわけ,蛋白質合成を阻害する効力を増強させるオリゴヌクレオチド組成物およびこれらの改良されたオリゴヌクレオチド組成物を製造し使用する方法を提供することにより,従来技術を進歩させるものである。
本発明の組成物中に組み込むためのアンチセンスまたは二本鎖RNAオリゴヌクレオチドは,標的遺伝子によりコードされる標的蛋白質の合成を阻害する。標的遺伝子は,細胞に対して内因性のものであっても外因性のもの(例えば,ウイルスによりまたは組換えDNA技術を用いて細胞内に導入される)であってもよい。本明細書において用いる場合,"標的遺伝子"との用語は,ポリペプチドをコードする領域を含むポリヌクレオチド,または複製,転写,翻訳,または標的蛋白質の発現に重要な他のプロセスを制御するポリヌクレオチド領域,または標的ポリペプチドをコードする領域および標的ポリペプチドの発現を制御する領域を含むポリヌクレオチドを含む。したがって,本明細書において用いる場合,"標的遺伝子"との用語は,例えば,目的とする遺伝子の転写により生成されるmRNA分子を表す。さらに,"標的遺伝子配列に対応するオリゴマー"におけるような"対応する"との用語は,2つの配列が相補的であるか,相同的であるか,または生物学的に合理的な他の関係を互いに有する(例えば,ヌクレオモノマーの配列およびその塩基対形成特性に基づいて)ことを意味する。
二本鎖RNA(二本鎖RNAまたはRNAi(二本鎖RNA干渉))とは,細胞において蛋白質合成を阻害するために用いることができる二本鎖RNAオリゴヌクレオチドである(例えば,WO01/36646A1;Elbashir et al.2001.Genes&Deveolpment 15:188;Elbashir et al.2001.Nature 411:494;Elbashir et al.2001 EMBO.20:6877を参照)。二本鎖RNAは,1つの自己相補的鎖または2つの別々の相補的鎖から形成することができる。デュープレックス形成は,標的遺伝子を含む細胞の内部で生じても外部で生じてもよい。
本明細書において用いる場合,"アンチセンスオリゴヌクレオチド"との用語は,標的ポリペプチドの合成を特異的に妨害するヌクレオチド配列を含むオリゴヌクレオチドを含む。一般に,本発明のアンチセンスオリゴヌクレオチドは,標的遺伝子(例えば,ポリヌクレオチド,例えば,DNA,mRNA(プレ−mRNAを含む))分子)のヌクレオチド配列の"センス"鎖に結合する。本発明のアンチセンスオリゴヌクレオチドが核酸分子に結合する場合,これらは核酸分子の任意の領域,例えば,イントロン,エクソン,5’または3’非翻訳領域に結合することができる。例えば,立体的傷害として作用するアンチセンスオリゴヌクレオチドは,核酸標的分子のスプライシングジャンクション,5’非翻訳領域,または開始領域に優先的に結合する。RNaseHを活性化することにより作用するアンチセンスオリゴヌクレオチドは,好ましくは核酸標的分子のイントロン,エクソン,5’非翻訳領域,または3’非翻訳領域中に結合する。
標的蛋白質を選択し,これをコードするヌクレオチド配列を決定した後,本発明の組成物に含めるオリゴヌクレオチドの配列を決定する。標的遺伝子の配列を分析し,排除工程と選択工程の両方を含む方法によりオリゴヌクレオチドを選択する。1つの態様においては,オリゴヌクレオチド中で連続していずれかのヌクレオチド(A,U,C,またはG)が4以上生ずるオリゴヌクレオチドを除く。別の態様においては,ジヌクレオチド反復(例えば,AUAU,ACAC,AGAG,UCUC,UGUG,またはCGCG)を有するオリゴヌクレオチドを除く。別の態様においては,好ましくは少なくとも約25ヌクレオチド離れている標的遺伝子のヌクレオチド配列を標的とするオリゴヌクレオチドを選択する。別の態様においては,オリゴヌクレオチドの塩基組成が類似するように,4−10個の各塩基を含むオリゴヌクレオチドを選択する。別の態様においては,オリゴヌクレオチド中のGまたはCである塩基のパーセントは50%より大きい。1つの態様においては,選択された標的配列に相補的であるようにオリゴヌクレオチドを設計する場合,好ましくは,これらは標的配列に100%相補的である。別の態様においては,オリゴヌクレオチドは好ましくは他の非標的遺伝子に対して3以上のミスマッチを有する。当業者は,利用可能なアラインメントプログラムおよび公共データベース,例えば,the National Institutes of Healthのインターネットウエブサイトを用いて,これを調べることができる。
本発明は,2以上の個々のオリゴヌクレオチド分子を含むオリゴヌクレオチド組成物に関する。組成物の個々のオリゴヌクレオチド分子は,1つの標的遺伝子の少なくとも1つの標的ヌクレオチド配列を標的とする。例えば,1つの態様においては,組成物中に存在するオリゴヌクレオチドの少なくとも2つは同じ標的遺伝子中の同じヌクレオチド配列を標的とする。例えば,オリゴヌクレオチドは,異なる化学を含むが標的核酸分子中の塩基の同じ配列を標的とする(例えば,これに特異的にハイブリダイズする)。別の態様においては,組成物中に存在するオリゴヌクレオチドの少なくとも2つは,同じ標的遺伝子中の異なるヌクレオチド配列を標的とする(例えば,オリゴヌクレオチド組成物は遺伝子のプロモーター中のヌクレオチド配列を標的とする1つのオリゴヌクレオチド,および標的核酸分子のコーディング配列の一部のヌクレオチド配列を標的とする別のオリゴヌクレオチドを含むか,あるいは,オリゴヌクレオチド組成物は,標的核酸分子のコーディング領域中の2つの異なるヌクレオチド配列を標的とする少なくとも2つの異なるオリゴヌクレオチドを含む)。
1つの態様においては,個々のオリゴヌクレオチドは,本発明の組成物に含有させる前に蛋白質合成を阻害する能力について個別に試験しない。
オリゴヌクレオチドおよびオリゴヌクレオチド組成物を1またはそれ以上の細胞と接触させ(すなわち,接触するようにする,本明細書においては投与する,またはデリバリーするとも称される),これに取り込ませる。"細胞"との用語には,原核生物細胞および真核生物細胞,好ましくは脊椎動物細胞,およびより好ましくは,哺乳動物細胞が含まれる。好ましい態様においては,本発明のオリゴヌクレオチド組成物はヒト細胞と接触させる。
コンジュゲート化剤はオリゴヌクレオチドに共有結合的に結合する。1つの態様においては,オリゴヌクレオチドをコンジュゲート化剤に結合させることにより誘導化するかまたは化学的に修飾して,細胞取り込みを容易にすることができる。例えば,コレステロール成分をオリゴヌクレオチドに共有結合させることにより,細胞取り込みを5から10倍改良し,これは次に,DNA結合を約10倍改良することができる(Boutorin et al.,1989,FEBS Letters 254:129−132)。オクチル,ドデシル,およびオクタデシル残基のコンジュゲーションは,未修飾オリゴヌクレオチドと比較して,細胞取り込みを3,4,および10倍増強させる(Vlassov et al.,1994,Biochimicaet Biophysica Acta 1197:95−108)。同様に,オリゴヌクレオチドをポリ−L−リジンで誘導化すると,細胞によるオリゴヌクレオチド取り込みを助けることができる(Schell,1974,Biochem.Biophys.Acta340:323,およびLemaitre eta l.,1987,Proc.Natl.Acad.Sci.USA84:648)。
カプセル化剤は,オリゴヌクレオチドをベヒクル中に封入する。別の態様においては,オリゴヌクレオチドは,担体またはベヒクル,例えば,リポソームまたはミセルと結合させることができるが,当業者により理解されるように,他の担体を用いてもよい。リポソームは,生物学的膜と類似する構造を有する脂質二重層から構成されるベヒクルである。そのような担体を用いて,オリゴヌクレオチドの細胞取り込みまたはターゲティングを容易にすることができ,またはオリゴヌクレオチドの薬物動力学または毒性学的特性を改良することができる。
複合体化剤は,強いが非共有結合的な力(例えば,静電的,ファンデルワールス,パイスタッキング相互作用等)でオリゴヌクレオチドに結合する。1つの態様においては,本発明のオリゴヌクレオチドを複合体化剤を用いて複合体化させて,オリゴヌクレオチドの細胞取り込みを増加させることができる。複合体化剤の例には,カチオン性脂質が含まれる。カチオン性脂質は,オリゴヌクレオチドを細胞にデリバリーするために用いることができる。
オリゴヌクレオチドのデリバリーはまた,オリゴヌクレオチドを細胞レセプターにターゲティングすることにより改良することができる。ターゲティング成分をオリゴヌクレオチドにコンジュゲート化するか,またはオリゴヌクレオチドに結合した担体基(すなわち,ポリ(L−リジン)またはリポソーム)に結合させることができる。この方法は,特定のレセプター媒介性エンドサイトーシスを示す細胞によく適している。
好ましくは,本発明のオリゴヌクレオチドを安定化する。すなわち,エンドヌクレアーゼおよびエキソヌクレアーゼ分解に対して実質的に耐性とする。オリゴヌクレオチドは,内因性細胞ヌクレアーゼによる攻撃に対して対応する未修飾オリゴヌクレオチドより少なくとも約3倍耐性が高い場合,ヌクレアーゼに対して実質的に耐性であり,少なくとも約6倍耐性が高い場合,高度にヌクレアーゼ耐性であると定義される。これは,当該技術分野において知られる手法を用いて,本発明のオリゴヌクレオチドがヌクレアーゼに対して実質的に耐性であることを示すことにより示すことができる。
本発明のオリゴヌクレオチドは,当該技術分野において知られる任意の方法により,例えば,酵素的合成および化学合成を用いて製造することができる。オリゴヌクレオチドは,インビトロ(例えば,酵素合成および化学合成を用いて),またはインビボ(当該技術分野においてよく知られる組換えDNA技術を用いて)で合成してもよい。
本発明はまた,細胞を上述のオリゴヌクレオチド組成物と接触させることを含む,細胞において蛋白質の発現を阻害する方法を特徴とする。
オリゴヌクレオチドの投与またはデリバリーの最適な経路は,所望の結果および/または治療すべき被験者によって様々である。本明細書において用いる場合,"投与"とは,細胞をオリゴヌクレオチドと接触させることを表し,これはインビトロで行ってもよく,インビボで行ってもよい。オリゴヌクレオチドの投与量は,標的核酸分子から翻訳される蛋白質の発現,例えば,過度の実験を行うことなくRNA安定性の読み出しによりまたは治療上の応答により測定される発現を,最適に減少させるように調節することができる。
本発明のオリゴヌクレオチド組成物は,遺伝子の発現を阻害することにより,蛋白質の発現が関与する任意の疾病を治療するために用いることができる。オリゴヌクレオチド組成物により治療することができる疾病の例には以下のものが含まれる:癌,網膜症,自己免疫疾患,炎症性疾病(例えば,ICAM−1関連疾患,乾癬,潰瘍性大腸炎,クローン病),ウイルス性疾病(例えば,HIV,C型肝炎),および心臓血管疾病。
実施例1.オリゴヌクレオチド組成物がA549細胞においてCDK2を阻害する能力
この実施例においては,5つの異なるアンチセンスオリゴヌクレオチドが個々にA549細胞においてCDK2の発現を阻害する能力を,5つすべてのアンチセンスオリゴヌクレオチドを一度にトランスフェクションした場合の能力と比較した。用いた5つのアンチセンスオリゴヌクレオチドの配列は以下のとおりである:
オリゴヌクレオチド1GCAGUAUACCUCUCGCU−CUUGUCAA(配列番号8);
オリゴヌクレオチド2UUUGGAAGUUCUCCAUGAA−GCGCCA(配列番号9);
オリゴヌクレオチド3GUCCAAAGUCUGCUA−GCUUGAUGGC(配列番号10);
オリゴヌクレオチド4CCCAGGAGGAUUU−CAGGAGCUCGGU(配列番号11);
オリゴヌクレオチド5UAGAAGUAACUCCU−GGCCACACCAC(配列番号12);
リバース対照AACUGUUCUCGCUC−UCCAUAUGACG(配列番号13)
図1は,培養細胞中の約30種の異なる遺伝子に対する約30回のアンチセンス阻害実験の結果の概要を示す。アンチセンスを実施例1に記載されるようにしてトランスフェクトし,標準的な方法を用いて,TaqmanリアルタイムPCRで阻害を分析した。それぞれの場合において,標的遺伝子に対してアンチセンスではない同じ化学の対照オリゴヌクレオチドとの比較によりアンチセンス阻害を決定した。アンチセンス組成物は,各遺伝子に対して設計した5−8個のアンチセンスオリゴヌクレオチドから構成され,個々のオリゴヌクレオチドを5またはそれ以上のアンチセンスオリゴヌクレオチドの混合物と比較した。3つの標的遺伝子については,混合物はよく作用せず,これらのデータは混合物の分析から排除した。顕著なことに,混合物は,最も良い個々のオリゴヌクレオチドとほぼ同等に(81−対84%)阻害した。すべての個々のオリゴヌクレオチドの平均阻害ははるかに低く(56%),変動ははるかに大きかった。すなわち,混合物を用いることにより,ほとんどの場合(標的遺伝子の約90%)に,最初に個々のオリゴヌクレオチドでスクリーニングして最も良く作用するオリゴヌクレオチドを選択することなく,高い阻害を得ることができる。また,個々のオリゴヌクレオチドを用いた場合に得られる結果の変動が増加することにより示されるように,多くの場合,混合物は最も良い個々のオリゴヌクレオチドより優れていた。
HeLa細胞を,1μg/mLのリポフェクタミン2000と複合体化した50nMのsiRNAで24時間トランスフェクションした。24時間後,細胞を溶解させ,RNAを単離してRT−PCRにより分析した。p53遺伝子のユニーク部位を標的とする7つのsiRNA複合体でトランスフェクションした。7つすべてのsiRNAの混合物(それぞれ等濃度)は"siRNAウルトラマー"と称される。対照の平均と比較して,最も良いsiRNA複合体は標的を87%阻害し,ウルトラマーは69%阻害した。
siRNA1:
CUGACUGCGGCUCCUCCAUTT (配列番号14)
AUGGAGGAGCCGCAGUCAGTT (配列番号15)
siRNA2:
CUCACAACCUCCGUCAUGUTT (配列番号16)
ACAUGACGGAGGUUGUGAGTT (配列番号17)
siRNA3:
GACCAUCGCUAUCUGAGCATT (配列番号18)
UGCUCAGAUAGCGAUGGUCTT (配列番号19)
siRNA4:
GUACAGUCAGAGCCAACCUTT (配列番号20)
AGGUUGGCUCUGACUGUACTT (配列番号21)
siRNA5:
ACCUCAAAGCUGUUCCGUCTT (配列番号22)
GACGGAACAGCUUUGAGGUTT (配列番号23)
siRNA6:
CCUCAUUCAGCUCUCGGAATT (配列番号24)
UUCCGAGAGCUGAAUGAGGTT (配列番号25)
siRNA7:
CCCUUCUGUCUUGAACAUGTT (配列番号26)
CAUGUUCAAGACAGAAGGGTT (配列番号27)
ヒト間葉幹細胞(hMSC)を,400nM(合計濃度,明確化のため,混合物中で各個別のオリゴマーは80nMであった)のsiRNAと複合体化した2μg/mLのリポフェクタミン2000でトランスフェクトした。GTP20(TD)を標的とする5つのsiRNAデュープレックス,マッチした対照デュープレックス(CD)の1つの組成物,および5つの各オリゴの等モル混合物("混合物")を24時間連続してトランスフェクションし,RNA Catcher(Sequitur,Inc.Natick,MA)を用いてRNAを回収した。GTP20 mRNAの発現はTaqmanにより定量し,GAPDHに対して標準化した。TD5(70%)およびウルトラマー(76%)を用いて,対照デュープレックスに対して70%またはそれ以上の阻害が得られた。
ヒトメサンギウム幹細胞(hMSC)を400nMのsiRNA(合計濃度,混合物中で各個別のデュープレックスは80nMである)と複合体化した2μg/mLのリポフェクタミン2000でトランスフェクトした。5つの標的化デュープレックス(TD),5つの対照デュープレックス(CD),1つの5デュープレックス等モル混合物("混合物")および1つの対照混合物(UC)を連続的に72時間トランスフェクションした。トランスフェクションの96時間後にRNA Catcherを用いてRNAを回収した。Cbfa−1 mRNAの発現はTaqmanにより定量し,GAPDHに対して標準化した。TD4を用いて対照デュープレックスの平均に対して70%またはそれ以上の阻害が得られた(74%)。混合物は,混合物対照と比較して70%阻害した。
TD1(s18883):AUUUAAUAGCGUGCUGCCATT (配列番号28)
TD2(s18885):CUGUAAUCUGACUCUGUCCTT (配列番号29)
TD3(s18887):AAUAUGGUCGCCAAACAGATT (配列番号30)
TD4(s18889):GUCAACACCAUCAUUCUGGTT (配列番号31)
TD5(s18891):AGGUUUAGAGUCAUCAAGCTT (配列番号32)
CD1(s18884):ACCGUCGUGCGAUAAUUUATT (配列番号33)
CD2(s18886):CCUGUCUCAGUCUAAUGUCTT (配列番号34)
CD3(s18888):AGACAAACCGCUGGUAUAATT (配列番号35)
CD4(s18890):GGUCUUACUACCACAACUGTT (配列番号36)
CD5(s18892):CGAACUACUGAGAUUUGGATT (配列番号37)
PTPミューmRNAを標的とする全ホスホロチオエートDNA25ntアンチセンスオリゴヌクレオチドのヒト肺癌腫(A549)細胞における効力。A549細胞を25nMのオリゴで16時間トランスフェクションした後,mRNAの強力な阻害が得られた。AS:アンチセンスオリゴヌクレオチド;RC:リバース対照;MIX:個々のASオリゴマーの混合物(総オリゴマー濃度25nM)。標的mRNAの量はGAPDHに対して標準化した。
ヒト臍帯静脈内皮細胞(HuVEC)中のPTP−PEST mRNAを標的とする25ntホスホロチオエートDNAアンチセンスオリゴヌクレオチドの効力。mRNAの阻害は,200nMのオリゴで細胞を4時間無血清トランスフェクションした後,血清含有培地中で14時間インキュベートした後に得た。AS:アンチセンスオリゴヌクレオチド;RC:リバース対照;混合物:個々のASオリゴマーの混合物(総オリゴ濃度200nM)。標的mRNAの量はGAPDHに対して標準化した。
正常ラット腎臓(NRK)細胞におけるPTP−イータmRNAを標的とする全ホスホロチオエートDNAの25ntアンチセンスオリゴヌクレオチドの効力。細胞を25nMのオリゴで一晩トランスフェクションした後にmRNAの阻害を測定した。AS:アンチセンスオリゴヌクレオチド;RC:リバース対照;Mix:個々のASオリゴマーの混合物(総オリゴマー濃度25nM)。標的mRNAの量はGAPDHに対して標準化した。
当業者は,日常的な実験を越えるものを使用せずに,本明細書に記載される本発明の特定の態様の多くの均等物を理解するかまたは確認することができる。そのような均等物は添付の特許請求の範囲に包含されることが意図される。
Claims (33)
- 標的遺伝子中の少なくとも3つの異なるヌクレオチド配列を標的とする少なくとも3つの異なるオリゴヌクレオチドを含むオリゴヌクレオチド組成物であって,(i)オリゴヌクレオチドは,それらの標的ヌクレオチド配列に高い親和性をもって結合し,かつ(ii)オリゴヌクレオチドはGC含量が高められていることを特徴とする組成物。
- オリゴヌクレオチドがアンチセンスオリゴヌクレオチドである,請求項1記載のオリゴヌクレオチド組成物。
- オリゴヌクレオチドが二本鎖RNAオリゴヌクレオチドである,請求項1記載のオリゴヌクレオチド組成物。
- オリゴヌクレオチド組成物が少なくとも約60℃のTmでそれらの標的ヌクレオチド配列に結合する,請求項1記載のオリゴヌクレオチド組成物。
- オリゴヌクレオチドが少なくとも約20%のGC含量を有する,請求項1記載のオリゴヌクレオチド組成物。
- 組成物が,少なくとも4個の異なる核酸配列を標的とする少なくとも約4個のアンチセンスオリゴヌクレオチドを含む,請求項1記載のオリゴヌクレオチド組成物。
- 組成物が,少なくとも5個の異なる核酸配列を標的とする少なくとも約5個のオリゴヌクレオチドを含む,請求項1記載のオリゴヌクレオチド組成物。
- 組成物が,少なくとも6個の異なる核酸配列を標的とする少なくとも約6個のオリゴヌクレオチドを含む,請求項1記載のオリゴヌクレオチド組成物。
- オリゴヌクレオチドが少なくとも約25ヌクレオモノマーの長さである,請求項1記載のオリゴヌクレオチド組成物。
- オリゴヌクレオチドが25ヌクレオモノマーの長さより長い,請求項1記載のオリゴヌクレオチド組成物。
- アンチセンスオリゴヌクレオチドの少なくとも1つは配列が標的ヌクレオチド配列に相補的である,請求項2記載のオリゴヌクレオチド組成物。
- アンチセンスオリゴヌクレオチドがRNaseHを活性化する,請求項2記載のオリゴヌクレオチド組成物。
- オリゴヌクレオチドの少なくとも1つが,少なくとも1つの修飾ヌクレオチド間結合を含む,請求項1記載のオリゴヌクレオチド組成物。
- オリゴヌクレオチドの少なくとも1つが,少なくとも1つの修飾糖成分を含む,請求項1記載のオリゴヌクレオチド組成物。
- 薬学的に許容しうる担体をさらに含む,請求項1記載のオリゴヌクレオチド組成物。
- オリゴヌクレオチド組成物が,組成物の最も有効な個別のオリゴヌクレオチドにより達成される阻害のレベルと同じまたはそれより高いレベルの蛋白質合成の阻害を達成する,請求項1記載のオリゴヌクレオチド組成物。
- 個別のオリゴヌクレオチドが,組成物中に取り込まれる前に蛋白質合成を阻害する能力について別々に試験されない,請求項1記載のオリゴヌクレオチド組成物。
- オリゴヌクレオチド組成物により,約80%より高い蛋白質合成の阻害が生ずる,請求項1記載のオリゴヌクレオチド組成物。
- 細胞において蛋白質合成を阻害する方法であって,細胞を,標的遺伝子中の少なくとも3つの異なるヌクレオチド配列を標的とする少なくとも3つの異なるオリゴヌクレオチドと接触させ,このことにより蛋白質合成を阻害することを含み,ここで,(i)オリゴヌクレオチドはその標的ヌクレオチド配列に高い親和性をもって結合し,および(ii)オリゴヌクレオチドはGC含量が高められていることを特徴とする方法。
- オリゴヌクレオチドがアンチセンスオリゴヌクレオチドである,請求項19記載の方法。
- オリゴヌクレオチドが二本鎖RNAオリゴヌクレオチドである,請求項19記載の方法。
- 方法がハイスループットのフォーマットで行われる,請求項19記載の方法。
- 蛋白質をコードする遺伝子の機能を同定する方法であって,細胞を,標的遺伝子中の少なくとも3つの異なるヌクレオチド配列を標的とする少なくとも3つの異なるオリゴヌクレオチドと接触させ,ここで,(i)オリゴヌクレオチドはその標的ヌクレオチド配列に高い親和性をもって結合し,および(ii)オリゴヌクレオチドはGC含量が高められており,そして,細胞において蛋白質発現の阻害により生ずる検出可能な表現型の変化をアッセイし,このことにより遺伝子の機能を決定する,ことを含む方法。
- オリゴヌクレオチドがアンチセンスオリゴヌクレオチドである,請求項23記載の方法。
- オリゴヌクレオチドが二本鎖RNAオリゴヌクレオチドである,請求項23記載の方法。
- 方法がハイスループットのフォーマットで行われる,請求項23記載の方法。
- 請求項1記載のオリゴヌクレオチド組成物を製造する方法であって,標的遺伝子中の少なくとも3つの異なるヌクレオチド配列を標的とする少なくとも3つの異なるオリゴヌクレオチドを組み合わせることを含み,ここで,(i)オリゴヌクレオチドはその標的ヌクレオチド配列に高い親和性をもって結合し,そして(ii)オリゴヌクレオチドはGC含量が高められており,かつ,個々のオリゴヌクレオチドを組成物中に組み込む前に蛋白質合成を阻害するそれらの能力について別々に試験しないことを特徴とする方法。
- オリゴヌクレオチドがアンチセンスオリゴヌクレオチドである,請求項27記載の方法。
- オリゴヌクレオチドが二本鎖RNAオリゴヌクレオチドである,請求項27記載の方法。
- 標的遺伝子中の少なくとも3つの異なるヌクレオチド配列を標的とする少なくとも3つの異なる二本鎖RNAオリゴヌクレオチドを含むオリゴヌクレオチド組成物。
- 細胞において蛋白質合成を阻害する方法であって,細胞を,標的遺伝子中の少なくとも3つの異なるヌクレオチド配列を標的とする少なくとも3つの異なる二本鎖RNAオリゴヌクレオチドと接触させることを含む方法。
- 蛋白質をコードする遺伝子の機能を同定する方法であって,細胞を,標的遺伝子中の少なくとも3つの異なるヌクレオチド配列を標的とする少なくとも3つの異なる二本鎖RNAオリゴヌクレオチドと接触させ,そして,細胞において蛋白質発現の阻害により生ずる検出可能な表現型の変化をアッセイし,このことにより遺伝子の機能を決定する,ことを含む方法。
- オリゴヌクレオチド組成物を製造する方法であって,標的遺伝子中の少なくとも3つの異なるヌクレオチド配列を標的とする少なくとも3つの異なる二本鎖RNAオリゴヌクレオチドを組み合わせることを含み,ここで,個々のオリゴヌクレオチドを組成物中に組み込む前に蛋白質合成を阻害するそれらの能力について別々に試験しないことを特徴とする方法。
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JP2011522523A (ja) * | 2008-05-16 | 2011-08-04 | セントレ・ナショナル・デ・ラ・レシェルシェ・サイエンティフィーク | 新規核酸移入系 |
JP2012514202A (ja) * | 2008-12-31 | 2012-06-21 | アボット ポイント オブ ケア インコーポレイテッド | ヌクレオチドコンジュゲートを使用する免疫測定法のための方法及び装置 |
US8445199B2 (en) | 2008-12-31 | 2013-05-21 | Abbott Point Of Care Inc. | Method and device for immunoassay using nucleotide conjugates |
US9207246B2 (en) | 2008-12-31 | 2015-12-08 | Abbott Point Of Care Inc. | Method and device for immunoassay using nucleotide conjugates |
US9964537B2 (en) | 2008-12-31 | 2018-05-08 | Abbott Point Of Care Inc. | Method and device for immunoassay using nucleotide conjugates |
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