JP2007501225A - 転移防止におけるsiRNAサイレンシングの使用 - Google Patents
転移防止におけるsiRNAサイレンシングの使用 Download PDFInfo
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Abstract
Description
欲しない遺伝子発現のサイレンス機構は正常細胞機能に非常に重要であり、RNAサイレンシングはこの10年で種々生命体の独立研究から合体した新規研究分野である。相同DNA配列及び/又はRNA配列間の相互作用により遺伝子をサイレンス化でき、DNAのメチル化を誘導することは長く知られている。(バーンステイン、イー(Berstein, E)、コーディ、エイエイ(Caudy, AA)、ハモンド、エスエム(Hammond, SM)、ハノン、ジージェー(Hannon GJ)、RNA妨害開始段階での二座リボヌクレアーゼの役割(Role for bidentate ribonuclease in the initiation step of RNA interference)、ネーチャー(Nature)、409巻、363−366頁(2001年))。1998年の線虫でのRNA妨害(RNAi)の発見により遺伝子サイレンシング誘発物として二重鎖RNA(dsRNA)に注意が集まり、現在植物の多くの遺伝子サイレンシング効果がdsRNA仲介であることが知られている。(バーンステイン、イー等(Berstein, E, et al)、RNA妨害開始段階での二座リボヌクレアーゼの役割(Role for bidentate ribonuclease in the initiation step of RNA interference)、ネーチャー(Nature)、409巻、363−366頁(2001年))。
現在癌は死の主原因のままであり、しばしば転移に帰結する。転移過程で腫瘍コロニーが最初の腫瘍(一次腫瘍)から脱離し、全身に広がった悪性細胞により確立する。転移形成は非常に複雑なプロセスであり、悪性細胞の一次腫瘍からの脱離、細胞外基質の侵入、内皮基底膜の侵入による体腔と血管へ入り、血液により運ばれた後の標的臓器への浸潤に依存する。最後に標的位での新規腫瘍の成長は血管新成に依存する。一次腫瘍を手術により除去できるが、手術処置後転移性沈着物が残ったり、一次腫瘍残遺物により発生する危険性が常にある。それ故転移防止が可能で癌患者に効果的治療を提供できる抗転移薬の必要性がある。
特許出願WO01/75164(A2)で体外系のショウジョバエを用いてdsRNAを長さがRNAセグメント21−23ヌクレオチド(nt)に加工することが示され、この21−23nt断片がRNA分解の特異的メディエーターであることを開示した。カプレン等(Caplan et al.)はCAT遺伝子と線虫―unc22遺伝子標的の合成siRNAが脊椎動物と無脊椎動物それぞれでの発現を減少することを報告している。(カプレン、エヌジェイ等(Caplan, N.J et al.)、”無脊椎動物と脊椎動物系における小さな二重鎖RNAによる遺伝子発現の特異的阻害”(Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems)、プロシーディングオブナショナルアカデミーオオブサイエンスユウエスエイ(Proc. Natl. Acad. Science. USA)、98巻(17号)、9742―47頁(2001年))。しかしWO01/7564も前出のプラン等(Caplan et al.)(2001年)のいずれも哺乳類のTF発現を直接調節できるsiRNAに関しては何も開示していない。ジャノブスキー(Janowsky)とシュベンザー(Schwenzer)(1998)はオリゴヌクレオチド促進者によるハンマーヘッド型リボソームの活性化を、とりわけハンマーヘッド型リボソーム作成物とhTF標的オリゴヌクレオチドプロモーターを例示した報告をしている。(ジャノブスキー(Janowsky, E,)及びシュベンザー(Schwenzer, B.)、”オリゴヌクレオチドプロモーターによりンマーヘッド型リボソームが多回ターンオーバー活性を持つ長いRNA基質を切断する能力(Oligonucleotide facilitators enable a hammerhead ribozyme to cleave long RNA substrates with multiple-turnover activity)、“ヨーロピアンジャーナルオブバイオケミストリー(Eur. J. Biochem.)、254巻、129−134頁(1998年))。しかしジャノブスキー(Janowsky)とシュベンザー(Schwenzer)が用いたハンマーヘッド型リボソームとオリゴヌクレオチドプロモーターによる遺伝子発現の阻害機構(ジャノブスキー(Janowsky, E,)及びシュベンザー(Schwenzer, B.)、1998年、前出)はsiRNAがTFコード化遺伝子のようないずれの遺伝子発現を阻害する機構とは明らかに異なる。
(a)SEQ ID NO1乃至SEQ ID NO8又はSEQ ID NO32乃至SEQ ID NO37で、その補体がSEQ IDNO48―SEQ ID 53で示される核酸配列を持つsiRNA分子、
(b)約90%が(a)のsiRNA分子に相同な配列を持つsiRNA分子、
(c)補体がSEQ IDNO48―SEQ ID 53であり、SEQ ID NO1乃至SEQ ID NO8又はSEQ ID NO32乃至SEQ ID NO37の5‘位又は3’位末端方向のいずれかで、ヌクレオチド7個までシフトした標的部位を持つ配列に妥協したsiRNA分子、
(d)約90%が(c)のsiRNA分子と相同なる配列を持つsiRNA分子、及び
(e)(a)―(d)の核酸配列を持つsiRNA分子で、配列がC1−C3アルキル基、C1−C3アルケニル基又はC1−C3アルキリル基を配列の一つ以上の2‘位OH水酸基に導入するか及び/又はリン酸ジエステル結合をチオリン酸エステル結合で置換して修飾しりことからなる一群から選ぶ。
ここで用いた用語“二重鎖”とはセンス鎖とアンチセンス鎖の両者を持つ核酸分子を意味する。このセンス鎖とアンチセンス鎖は同一核酸分子からでも或いは二つの核酸分子から構築し且つリンカー分子(例えばポリヌクレオチドリンカーか非ヌクレオチドリンカー)で共有結合しても良い。
図1は、siRNA、レポーター作成物及び導入遺伝子発現のRNAiを示す。a)ヒトTF(ジェンバンク参加受入番号M16553)mRNA内の八個所を標的とするsiRNA種のセンス(上側)鎖とアンチセンス(下側)鎖を示す。b)ヒトTFのルシフェラーゼレポーター作成物及びc)同時形質移入アッセイのsiRNAによるRNAi(それぞれ3通りで、三回以上の独立実験の平均その標準偏差(s.d.)を示す)。
RNAiはsiRNA導入により始まる転写後遺伝子サイレンシングの形である。短い21乃至25個のヌクレオチド二重鎖RNAは線虫(ザモーア等(Zamore, et al)、セル(Cell)、101巻、25−33頁(2000年))や哺乳類組織培養株細胞(エルバシャー等(Elbashir et al.)、ネーチャー(Nature)、411巻、494−498頁(2001年))で下方制御遺伝子発現に有効である。哺乳類でのこのやり方の更なる治療的有効性がマッカフリー等により更に体内で示された。(ネーチャー(Nature)、418巻、38−39頁(2002年))。TFのような哺乳類遺伝子の核酸配列を用いて使用の特異的21乃至25個のヌクレオチドRNA配列を持つTF標的遺伝子を不活性化する小さな妨害RNA(siRNA)をデザインできる。TFを標的とするsiRNAを、例えば治療薬として用いて凝固障害や転移腫瘍を防止するのに使用できる。
他の形のオリゴヌクレオチドで糖はヌクレオシド内結合、即ちバックボーンを両者の新規な基で置換する。この種分子の一つはペプチド核酸(PNA)と呼ぶ。PNA化合物はアミドバックボーン、より具体的にはアミノエチルグリシンバックボーンを含有する。核酸塩基は保持され、バックボーンのアミド部のアザ窒素原子と直接又は間接的に結合する。この核酸塩基オリゴマーの作成法と使用法は、例えばニールセン、ピーイー編(Neilsen, P.E. Ed.)“ペプチド核酸:手順と応用(Peptide Nucleic Acids: Protocols and Applications)”、ホライゾン出版(Horizon Press)、ノーフォーク(Norfolk)、英国(United Kingom)、1999年に記載されている。PNA作成法は例えば米国特許5,539,082、5,714,331及び5,719,162に開示されており、それぞれをここに文献として取り入れる。
siRNA分子の操作と取り扱いを簡単化する方法の一つはsiRNA分子をコード化するcDNAカセットを適切なプロモーター制御下に置くことである。プロモーターは所望の標的ホスト細胞のsiRNA発現を促進するに違いない。適切なプロモーターの選択は容易に達成できる。好ましくは高度な発現プロモーターを用いる。適切なプロモーターの例としては規定配列の転写物を生成できる自給型重合酵素IIIプロモーターU6か又は1を含む。適切な重合酵素IIプロモーター例としえは763―塩基対サイトメガロウイルス(CMV)プロモーターがある。
最近DNA鋳型法を用いてsiRNA分子が創製送達された。(ツッシュル、ティ(Tuschl, T.)、ネーチャーバイオテクノロジー(Nature Biotechnology)、20巻、446−448、(2002年)に概説)。siRNA鋳型を通常小さい細胞核RNAU6かヒトRNAseP RNAH1をコード化するRNAポリメラーゼIII転写単位にクローンする。これら発現カセットによりセンスRNAとアンチセンスRNAの両者が発現できる。導入DNA鋳型によるsiRNAの内在性発現は外因性siRNAデリバリーのある限度、特に表現形の一過性喪失に打ち勝つと考えられる。事実これらsiRNA発現カセットを用いて機能表現形の安定に喪失した安定な株細胞を得た。(宮岸および平良(Myagishi M. and Taira K.)、ネーチャーバイオテクノロジー(Nature Biotech)、20巻497−500頁(2002年)、ブラッメルカンプ、ティアール等(Brummelkamp, T.R. et al.)、サイエンス(Science)、296巻、550−553頁(2002年))。もし望むなら上記の方法でTFのRNAi用の安定な株細胞も生成できる。
mRNAとタンパク質発現は限定はされないがノーザンブロット分析、RNAse保護アッセイ、ルシフェラーゼ又はβガルレポーターアッセイ、ウェスタンブロット及びELISAのような免疫法を含む種々の既知の技術的方法で分析できる。
本発明によるsiRNAを用いて哺乳類TFの発現や生物活性を下方制御できる。従って本発明のRNAを用いて限定はされないがヒト、ウシ、ウマ、ブタ、ヒツジ、鳥、マウス、ラット、イヌ、ネコ、サル、ヒヒや類似体を含む温血動物の腫瘍転移を治療や防止できる。治療は通常病院で始まるので、医師が治療効果を間近に観察し必要ないずれかの調節を行える。治療期間は治療腫瘍転移、患者の年齢と状態、患者疾患の段階と形及び治療に対し如何に患者身体が応答するかに依存する。治療を異なる間隔(例えば毎日、毎週又は毎月)で実施できる。治療を患者身体が健康な新規細胞を作り力を回復する機会があるように断続的周期でもできる。
ヒトTF(hTF)サイレンシングを得るsiRNAを提供するため、21個のヌクレオチドRNAをPCT/NO03/00045に記載のようにホスホラミダイト(ファルマシアアンドエイビーアイ(Pharmacia and ABI))を用いて化学的に合成した。hTFmRNAに対する13個のsiRNAを合成した。(ウイガー、エムティ(Wiiger MT)、プリングル、エス(Pringle S)、ペターソン、ケイエス(Pettersen KS)、奈良原(Narahara N)、プリッズ、エッチ(Pryddz H.)、ヒト内皮細胞における誘導組織因子へのリガンド(FVII)結合の効果(Effects of binding of ligand (FVIIa) to induced tissue factor in human endothelial cells.)、トロンボリサーチ(Thromb Res.)、98巻、311−321頁(2000年))(図1a)。これらsiRNAの八個をそれぞれSEQ ID NO1からSEQ ID NO8と名付ける。本発明はとりわけPCT/NO03/00045に開示のSEQ ID NO1からSEQ ID NO31による合成siRNAの使用に関する。
TFsiRNA効率の初期分析を二重ルシフェラーゼ系(プロメガ(Promega))を用いてhTF−LUC(図1b)とhTFsiRNA(図1a)で一過的に同時形質移入したHeLa細胞で実施した。LUC発現とRluc発現の比を代表的な関係siRNAであるプロテインセリンキナーゼ314i(PSK314i)で形質移入した細胞レベルに正規化した。
最良siRNA(即ちhTF167i)の標的位周囲領域でより高度な解決へ到達できるかを調べた。siRNA(hTF158i,hTF161i、hTF164i、hTF170i、hTF173i及びhTF176i)をhTF167の両側に3nt増分だけシフトした部位を標的年、それぞれが21ntの内18ntをその隣接物と共有するように合成した。(図1c)。驚くべきことにこれらsiRNA間の配列と位置差が最小にもかかわらず、広範囲の活性を示すことが見られた。(図2)。上流siRNAではより顕著なhTF167iの全活性が徐々に遠ざかる変化が起こる。二つのsiRNAのhTF158iとhTF161iはそれぞれhTF167iから9個と6個のヌクレオチドだけ遠ざかるようにシフトするが、その活性は大幅に減少した。この結果は一つ又は複数の局所因子が位置効果を起こすことを示唆する。
基質としてレポーター遺伝子の強制発現を用いた同時形質移入アッセイの結果は説明しにくい。siRNAの効果をそれ故TFを恒常的に発現するHaCaT細胞の内在性mRNAにおいて測定した。(図3a)。二つの最良高TF siRNAのhTF167iとhTF372iはこのアッセイで強活性を示し、正規化TFmRNAはそれぞれ10%と26%に減少した。(図3a)。興味あることにRNAiに基づくmRNAの開裂アッセイでは今のところ哺乳類系では失敗しているが、サイズは標的配列の一次開裂物と一致する開裂産物が減少した主バンドの下に明白に現れた。(ツシュル、ティ(Tuschl, T)、ザモーア、ピーディ(Zamore PD)、レーマン、アール(Lehman R)、バーテル、ディピー(Bartel DP)、シャープ、ピーエイ(Sharp PA)、二重鎖RNAによる体外での標的mRNAの分解(Targeted mRNA degradation by double-stranded RNA in vitro)、ジーンデベロプメント(Gene Dev.)、13巻、3191−3197頁(1999年))。従って本発明は哺乳類細胞のmRNAを開裂できるsiRNAと関連する。更に観察効果はRISCが又哺乳類でも活性であることを示唆する。同時形質移入アッセイの三番目に良いsiRNAのhTF256iは又TFmRNAレベルを著しく減少した。(残留発現は57%、データは示してない)。残留TFsiRNAはノーザンアッセイによる測定で活性を全く示さず(図3b)、TF発現も又刺激しなかったが、ある興味ある点では、化学修飾リボソームの形質移入によりTFmRNA誘導は三倍になった。(データは示してない)。従って関連siRNAの相対的不活性(即ち非特異的効果を持つsiRNA)は更にsiRNAベースの薬の期待を強める。
mRNAサイレンシングの時間経過を測定し、形質移入開始4,8、24及び48時間後回収の細胞ノーザン分析では24時間後に最大のsiRNAサイレンシングを示した。(図5a)。hTF167iはhTF173iに比し各時間点でmRNAレベルをより減少したので、見かけの減少速度に差があるように思われる。類似のことがhTF167iの修飾バージョンでも観察され、誘導突然変異(M1とM2)により阻害効率が減少した。アンチセンス鎖での突然変異はセンス鎖での相当の突然変異よりより明白な効果があった。siRNA誘導による標的分解が不完全であるという事実(最も有効なsiRNAでも残留標的mRNAが約10%のレベル)は、保護区画、即ちスプライソソームか他の細胞核位置のmRNA区画の存在によるのであろう。しかし上のデータと競争実験データの観点から、分解は時間のかかるプロセスなので、転写と分解間の動力学な決定のバランスによる可能性が高い。植物(パラッキ、ジェイシー(Palauqui JC)、バルゼルグ、エス(Balzergue S)、DNAの局所的導入による全身確保のサイレンシングの活性化(Activation of systemic acquired silencing by localized introduction of DNA)、カレントバイオロジー(Curr Biol.)、9巻、59−66頁(1999年)及び線虫(ファイヤー、エイ(Fire, A.)、RNA引き金による遺伝子サイレンシング(RNA-triggered gene silencing)、トレンドジェネティック(Trends Genet.)、15巻、358−363頁(1999年)、グリショック、エイ(Grishok, A.)、田原(Tahara, H.)、メロー、シーシー(Mello CC)、線虫RNAi遺伝での遺伝子的必要性(Genetic requirements for inheritance of RNAi in C. elegans)、サイエンス(Science)、287巻、2494−2497頁(2000年))での実験によりあるsiRNA遺伝子が誘導表現形の遺伝力と関連する系の存在が示唆された。哺乳類細胞でのこの繁殖体の存在を調べるため、非常に低細胞密度で形質移入したHaCaT細胞でのsiRNAサイレンシングの持続性を測定した。レポーター作成物の連続形質移入に基づく実験で、形質移入後3日と5日の間で発現が徐々に回復し、内因性TFmRNAに対するsiRNA効果の時間依存性は同等であった。(図5b)。模倣形質移入制御細胞のTFmRNAレベルは実験経過とともに徐々に低下し、発現の細胞増殖依存の下方制御であるように思われる。興味あることに凝血原活性は形質移入細胞制御レベルに回復する兆しを殆ど示さない。(図5b、列)。同様のことがhTF372iとhTF167i、hTF372i及びhTF562iの組み合わせで見られた。(データは示してない)。
前述のごとく突然変異が全siRNA内で等しく許容できるのかどうかを決めるため、siRNAをより体系的に位置づけした。全部で8つの異なる新規一重突然変異体siRNAをデザインし、突然変異(s1、s2、s3、s4,s7、s13、s16、即ちSEQ ID NO9−17)の位置(センス鎖の5‘位から開始)に従い名付けた。前述の中央一重突然変異体M1(実施例4)をこの分析に加えs10と改名した。全siRNAを変性ポリアクリルアミドゲル電気泳動(PAGE)(15%)変性により増殖アニーリングを分析した。
siRNA鎖の極限5‘位と3’位末端それぞれ一個修飾した一連のsiRNA(P1+1、M1+1、A1+1、即ちそれぞれSEQ ID NO 22とその補体SEQ ID NO 38、SEQ ID NO 26とその補体SEQ ID NO 42、SEQ ID NO 30とその補体SEQ ID NO46を先ず合成した。化学合成siRNAの5‘位末端は活性になる体内でリン酸化されねばならないので、修飾により鋭敏であろう。(ニーカネン、エイ(Nykanen, A.)、ヘイリー、ビー(Haley, B.)及びゼイモアー、ピーディ(Zamore, P.D.)、RNA妨害経路におけるATPの必要性と小さな妨害RNA構造(ATP Requirements and Small Interfering RNA Structure in the RNA Interference Pathway)、セル(Cell)、107巻、309−321頁(2001年))。それ故種々なタイプの修飾を許容できる非塩基対3’位オーバーハングでのみ二修飾したsiRNA(siRNA P0+2、M0+2及びA0+2、即ちそれぞれSEQ ID NO23、27及び31、図6参照)を含めた。(エルバシャー、エスエム(Elbashir SM)、ハーボース、ジェイ(Harborth J)、レンデケル、ダブリュ(Lendeckel W)、ヤルシン、エイ(Yalcin A)、ウェバー、ケイ(Weber K)、ツシュル、ティ(Tuschl T)、培養哺乳類細胞における21個のヌクレオチドRNA二本鎖によるRNA妨害の仲介(Duplexes of 21-nucleotide RNAs medate RNA interference in cultured mammalian cells)、ネーチャー(Nature)、411巻、494−498頁(2001年)、エルバシャー、エスエム(Elbashir SM)、マーティネス、ジェイ(Martinez, J.)、パニカニオブスカ、エイ(Patkaniowska, A.)、レンデケル、ダブリュ(Lendeckel W)及びツシュル、ティ(Tuschl T)、“キイロショウジョバエ胚溶解物における有効RNAi仲介に関するsiRNAの機能分析”(Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate)、EMBOジャーナル(EMBO J.)20巻、6877−6888頁)(2001年)、エルバシャー、エスエム(Elbashir SM)、レンデケル、ダブリュ(Lendeckel W)及びツシュル、ティ(Tuschl T)、21と22nt RNAによるRNA妨害の仲介(RNA Interference is mediated by 21 and 22 nt RNAs)、ジーンデベロプメント(Gene Dev.)、15巻、188−200頁(2001年))。形質移入HaCaT細胞のノーザン分析により両末端をアリール化したsiRNA以外は、実質的に全修飾siRNAの活性が減少しないことが示された。(図8)。3‘位末端でのアリール基修飾のみでは活性に対する効果は無かった。5’位末端ヌクレオチドの2‘位水酸基に大きな置換基が存在すると、ニーカネン等が必要性を示したsiRNAの適切なリン酸化が妨害されるのであろう。(ニーカネン、エイ(Nykanen, A.)、ヘイリー、ビー(Haley, B.)及びゼイモアー、ピーディ(Zamore, P.D.)、RNA妨害経路におけるATPの必要性と小さな妨害RNA構造(ATP Requirements and Small Interfering RNA Structure in the RNA Interference Pathway)、セル(Cell)、107巻、309−321頁(2001年))。
組織因子(TF)のノックダウンにより尾静脈注入細胞のマウスの肺循環での定着と肺腫瘍を形成能を低下しするかどうかを調べるための実験をデザイン実施した。注射に対照マウスのTFレベルを10−20%低下したノックダウン細胞を注射する前にマウスTFに対するsiRNAを細胞に形質移入した。細胞に注射の6−25日後にマウスを犠牲にした。0.2ml培地に20万乃至100万個の細胞を各マウスに注入した。使用マウスは全てhC57B1あった。三つのグループについて各実験を試験した。グループ1:注入前の細胞を未知機能のセリンキナーゼのPSKH1に対するsiRNAで前処理。グループ2:細胞をマウスTFに対するsiRNAで前処理。グループ3:細胞をヒトTFに対するsiRNAで前処理。マウスの検死後肺の肉眼で可視の腫瘍数を数えた。結果の例を表1と2に示す。マウスTFに対するsiRNAで処置のマウスの受け入れ細胞(グループ2)は低い数字の腫瘍を発現する。グループ1のマウスはグループ2のマウスに比し約10倍以上の腫瘍を発現し,
グループ3のマウスはその肺に500個以上の腫瘍を有する。標的mRNAに対するRNAの効果は非常に特異的であるので(もしRNA配列を他のヌクレオチド配列と結合しないように適切に選択している場合)、グループ3のマウスはグループ2のマウスに比し肺腫瘍は200−250倍迄増加するであろう。この実験により注入細胞のTFレベルは非常に特異的効果、即ち肺での腫瘍形成能を増加することが示された。
この実施例は実施例7の検証を表す。hTFの最適siRNA標的をかくまう領域に200bp以内で対応する位置の部位を標的とするマウスTF(mTF)に特異的な8つのsiRNAをデザインした。(ホレン、ティ等(Holen, T. et al)、前出(2002年))。100nMsiRNAによるB16細胞のリポフェクタミン2000仲介形質移入では異なる標的配列によ効率が非常に変化することが示され、以前の観察と一致した。(ホレン、ティ等(Holen, T. et al)、前出(2002年))。二つの最も有効なsiRNAのmTF223iとmTF321iは培養B16細胞でmTFmRNAを常に70−80%減少した。
実施例7と8でTFのノックダウンがB16メラノーマ細胞による肺コロニー形成を防ぐことが示された。本発明者は更にTF標的siRNAの効果も又siRNAの全身注入後も明白で、siRNAの治療使用の可能性を示した。(図11参照)。hTF167iを負の対照に用いた。
アンニールしたsiRNA1050μl(50μM,50μg/ml)+オプティメム(OptiMEM)6500μl
リポフェクタミン2001500μl+オプティメム(OptiMEM)6000μl
5分後二つの溶液を一緒にし、注入前に20分間保温した。注入に際し対照siRNA用混合物を10mMトリス(Tris)、pH7.5で置換した。
Claims (22)
- 転移防止に有効な薬組成作成として組織因子(TF)標的の一つ以上の短い妨害RNA分子(siRNA)の使用。
- TF又はその断片が脊椎動物起源、好ましくは哺乳類起源、より好ましくはヒト起源である請求項1の使用。
- siRNAが少なくとも19のヌクレオチドからなる一重鎖siRNAか二重鎖siRNAで、且つ核酸配列かその断片をコード化する組織因子に向かい、siRNA分子が
(a)SEQ ID NO1乃至SEQ ID NO8又はSEQ ID NO32乃至SEQ ID NO37で、その補体がSEQ ID NO48―SEQ ID NO53で示す核酸配列を持つsiRNA分子、
(b)(a)のsiRNA分子に約90%相同な配列を持つsiRNA分子、
(c)標的部位が補体がSEQ ID NO48―SEQ ID NO53で、SEQ ID NO1乃至SEQ ID NO8又はSEQ ID NO32乃至SEQ ID NO37の5‘位か3’位末端方向のいずれかにヌクレオチド7個までシフトした配列を含むsiRNA分子、
(d)(c)のRNA分子に約90%相同な配列を持つsiRNA分子、および
(e)配列がC1−C3アルキル、C1−C3アルケニル又はC1−C3アルキリル基を配列の一つ以上の2‘位OH水酸基に導入して修飾するか、又はリン酸ジエステル結合をチオリン酸結合で置換修飾した(a)―(d)の核酸配列を持つsiRNAからなるグループから選択する請求項1と2のいずれかの使用。 - このsiRNAが二重鎖である請求項1の使用。
- このsiRNAが長さ21乃至25個のヌクレオチド、好ましくは長さ21個のヌクレオチドである請求項1の使用。
- このsiRNAがSEQ ID NO1乃至SEQ ID NO8で特定される請求項1乃至5のいずれかの使用。
- siRNAがmRNA開裂を誘導する請求項1乃至6のいずれかの使用。
- siRNAがSEQ ID No1かSEQ ID No煮で特定される請求項7の使用.
- siRNAがSEQ ID NO10乃至31で示される配列の請求項8の使用。
- 配列がC1−C3アルキル、C1−C3アルケニル又はC1−C3アルキリル基を配列の一つ以上の2‘位OH水酸基に導入修飾する請求項9の使用。
- siRNAがSEQ ID NO9、10又は11で示される配列である請求項10の使用。
- 配列がリン酸ジエステル結合をチオリン酸結合で置換修飾する請求項11の使用。
- siRNA分子がSEQ ID NO24でその補体がSEQ ID NO40、SEQ ID NO28でその補体がSEQ ID NO44、又はSEQ ID NO29でその補体がSEQ ID NO45で示される配列である請求項12のRNA分子(siRNA)。
- siRNA分子がSEQ ID NO29でその補体がSEQ ID NO45で示される配列である請求項13の使用。
- 薬組成が任意に例えば希釈剤、潤滑剤、結合剤、担体崩壊手段、吸収手段、着色剤、甘味剤及び/又は風味剤を含む請求項1乃至14のいずれかの使用。
- 組成が賦活剤及び/又は他の治療方針を含む請求項1乃至15のいずれかの使用。
- 薬組成が非経口(皮下、静脈内、筋肉内、腹腔内注射か点滴)、経口、経鼻、頬側、直腸、膣投与用に処方した請求項1乃至16のいずれかの使用。
- この薬組成が在来の無毒性薬剤容認の担体、補助剤及び/又は媒体含有の用量処方で、例えば点滴溶液や点滴懸濁液、エアロゾル、カプセル、錠剤、丸薬、噴霧、座薬などとして処方した請求項1乃至17のいずれかの使用。
- この薬組成を一回用量、分割用量で又は持続性放出処方により投与する請求項1乃至18のいずれかの使用。
- この薬組成を単独か他の薬と一緒に投与する請求項1乃至19のいずれかの使用。
- siRNAがSEQ ID NO32乃至SEQ ID NO37でその補体がそれぞれSEQ ID NO48乃至SEQ ID NO53で特定される請求項1乃至5のいずれかの使用。
- SEQ ID NO32乃至SEQ ID NO37でその補体がそれぞれSEQ ID NO48乃至SEQ ID NO53で示される核酸配列を持つことを特徴とするsiRNA。
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NO20033492A NO20033492D0 (no) | 2003-08-06 | 2003-08-06 | Bruk av siRNA i avstengning av gener for å hindre utvikling av metastaser |
US49731403P | 2003-08-25 | 2003-08-25 | |
PCT/NO2004/000238 WO2005040187A2 (en) | 2003-08-06 | 2004-08-05 | The use of sirna silencing in the prevention of metastasis |
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JP2002514201A (ja) * | 1997-01-22 | 2002-05-14 | ボード オブ リージェンツ,ザ ユニバーシティ オブ テキサス システム | 凝固および腫瘍の処置のための組織因子の方法および組成物 |
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WO2001005353A2 (en) * | 1999-07-14 | 2001-01-25 | Novo Nordisk A/S | USE OF FVIIa OR A TISSUE FACTOR ANTAGONIST FOR REGULATING GENE EXPRESSION AND CELL MIGRATION OR CHEMOTAXIS |
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