JP2021101709A - サイズが減少した自己送達用RNAi化合物 - Google Patents
サイズが減少した自己送達用RNAi化合物 Download PDFInfo
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Abstract
Description
本願は、2008年9月22日に出願された米国仮出願第US 61/192,954号、表題「Chemically Modified Polynucleotides and Methods of Using the Same」、2009年2月4日に出願された同第US 61/149,946号、表題「Minimum Length Triggers of RNA Interference」、および2009年7月8日に出願された同第US 61/224,031号、表題「Minimum Length Triggers of RNA Interference」の、35 U.S.C.§119(e)に基づく利益を主張する。これらの各々の開示は、その全体において本明細書において参考として組み込まれる。
本発明は、RNA干渉(RNAi)の分野に関する。本発明は、より具体的には、送達剤を使用しない、改善されたin vivo送達特性を有する核酸分子、および効率的な遺伝子サイレンシングにおけるそれらの使用に関する。
相補的なオリゴヌクレオチド配列は、有望な治療剤であって、遺伝子の機能を解明する上での有用な研究ツールである。しかし、先行技術のオリゴヌクレオチド分子は、その臨床的開発を妨げる可能性があるいくつかの問題に悩まされており、これは、かかる組成物を用いてのin vivoでの遺伝子発現(タンパク質合成を含む)の意図した効率的な阻害を達成することをしばしば困難にする。
本明細書において記載されるのは、最短の二本鎖領域を有する、非対称な化学修飾された核酸分子、および遺伝子サイレンシングにおけるかかる分子の使用である。本発明に関するRNAi分子は、一本鎖領域および二本鎖領域を含み、分子の一本鎖領域および二本鎖領域の両方において、多様な化学修飾を含み得る。さらに、RNAi分子は、従来のおよび先進的なステロール型分子などの疎水性抱合体に結合してもよい。この新たなクラスのRNAi分子は、in vitroおよびin vivoの両方において、先に記載されたRNAi分子よりも、優れた効力を有する。
ガイド鎖、ここで、前記ガイド鎖は、16〜28ヌクレオチド長であり、標的遺伝子に対して相補性を有し、ここで、前記ガイド鎖の3’末端の10ヌクレオチドは、少なくとも2個のリン酸修飾を含み、およびここで、前記ガイド鎖は5’リン酸修飾を有し、少なくとも1つの2’O−メチル修飾または2’−フルオロ修飾を含む、ならびに、
パッセンジャー鎖、ここで、前記パッセンジャー鎖は、8〜14ヌクレオチド長であって、前記ガイド鎖に対する相補性を有し、ここで、前記パッセンジャー鎖は親油性基に結合している、
を有する単離された二本鎖核酸分子であって、ここで、前記ガイド鎖および前記パッセンジャー鎖は、二本鎖核酸分子を形成する、前記二本鎖核酸分子である。
一部の態様において、ガイド鎖は、18〜19ヌクレオチド長である。他の態様において、パッセンジャー鎖は、11〜13ヌクレオチド長である。
二本鎖核酸分子は、他の態様において、平滑であるか、または1〜2ヌクレオチドの突出を含む1つの末端を有する。
第1のポリヌクレオチド、ここで前記第1のポリヌクレオチドは、第2のポリヌクレオチドおよび標的遺伝子に対して相補的である;および
第2のポリヌクレオチド、ここで、前記第2のポリヌクレオチドは、前記第1のポリヌクレオチドよりも少なくとも6ヌクレオチド短い、
を有し、ここで前記第1のポリヌクレオチドは、40〜90%の疎水性塩基修飾、40〜90%のホスホロチオエートおよび40〜90%のリボース部分の修飾または任意のこれらの組み合わせからなる群より選択される修飾を含む一本鎖領域を含む。
第1のポリヌクレオチド、ここで、前記第1のポリヌクレオチドは、第2のポリヌクレオチドおよび標的遺伝子に対して相補的である;および
第2のポリヌクレオチド、ここで、前記第2のポリヌクレオチドは、前記第1のポリヌクレオチドよりも少なくとも6ヌクレオチド短い、
を有するデュプレックスポリヌクレオチドであって、ここで、前記デュプレックスポリヌクレオチドは、前記第1のポリヌクレオチド上のヌクレオチド9、11、12、13または14と前記第2のポリヌクレオチド上の反対のヌクレオチドとの間にミスマッチを含む、前記デュプレックスポリヌクレオチドである。
疎水性修飾ポリヌクレオチド、ここで、前記ポリヌクレオチドは二本鎖RNAであって、疎水性分子に結合し、ここで、前記二本鎖核酸分子は、ガイド鎖およびパッセンジャー鎖を含み、ここで、前記ガイド鎖は16〜29ヌクレオチド長であって、標的遺伝子に対して実質的に相補性であり、ここで、前記パッセンジャー鎖は、8〜14ヌクレオチド長であって、前記ガイド鎖に対して相補性を有し、ここで、ガイド鎖の1位は、5’リン酸化されているかまたは2’O−メチル修飾を有し、ここで、前記二本鎖核酸のヌクレオチドのうち少なくとも40%は修飾されており、およびここで、前記二本鎖核酸分子は、平滑である一つの末端を有するか、または1〜2ヌクレオチドの突出を含む、前記疎水性修飾ポリヌクレオチド;
中性脂質混合物;
および任意に、カーゴ分子
を有する前記組成物であって、ここで、前記疎水性修飾ポリヌクレオチドおよび前記中性脂質混合物がミセルを形成する、前記組成物が、本発明の他の側面において提供される。
一部の態様において、ポリヌクレオチドは、化学修飾を含む。例えば、これは少なくとも40%修飾されていてもよい。
他の態様において、対象は、ヒトである。他の態様において、標的遺伝子は、PPIB、MAP4K4またはSOD1である。
一部の態様において、ガイド鎖は、16、17、18、19、20、21、22、23、24、25、26、27、28または29ヌクレオチド長である。一部の態様において、パッセンジャー鎖は、8、9、10、11、12、13または14ヌクレオチド長である。一部の態様において、核酸分子は、−20kkal/mol未満の熱力学的安定性(ΔG)を有する。
ガイド鎖、ここで、前記ガイド鎖は、16〜28ヌクレオチド長であり、標的遺伝子に対して相補性を有し、ここで、前記ガイド鎖の3’末端の10ヌクレオチドは、少なくとも2個のリン酸修飾を含み、ここで、前記ガイド鎖は、少なくとも1つの2’O−メチル修飾または2’−フルオロ修飾を含む、ならびに、
パッセンジャー鎖、ここで、前記パッセンジャー鎖は、8〜28ヌクレオチド長であって、前記ガイド鎖に対して相補性を有し、ここで、前記パッセンジャー鎖は親油性基に結合している、
を含む単離された二本鎖核酸分子であって、ここで、前記ガイド鎖と前記パッセンジャー鎖は、二本鎖核酸分子を形成する、前記二本鎖核酸分子に関する。
添付の図面は、原寸で描画されることを意図されていない。図面において、多様な図において示される各々の同一またはほぼ同一の成分は、類似の数詞により表わされる。明確化を目的として、全ての成分が全ての図面においてラベルされているわけではない。図面においては以下のとおりである。
本発明の側面は、遺伝子サイレンシングに関与する方法および組成物に関する。本発明は、少なくとも部分的に、8〜14ヌクレオチドなどの最短の長さの二本鎖領域を有する非対称核酸分子が、遺伝子発現をサイレンシングする上で有効であるという驚くべき発見に基づく。かかる短い二本鎖領域を有する分子がRNA干渉を媒介する上で有効であることは、以前には示されていない。以前には、19ヌクレオチドまたはそれより長い二本鎖領域が存在しなければならないと推測されていた。本明細書において記載される分子は、化学修飾を通して、一部の例においては疎水性抱合体の結合を通して、最適化される。
本明細書において用いられる場合、「2’−修飾されたリボース糖」は、2’−OH基を有さないリボース糖を含む。「2’−修飾されたリボース糖」は、(未修飾の基準のDNAヌクレオチドにおいて見出される)2’−デオキシリボースを含まない。例えば、2’−修飾されているリボース糖は、2’−O−アルキルヌクレオチド、2’−デオキシ−2’−フルオロヌクレオチド、2’−デオキシヌクレオチド、またはこれらの組み合わせであってもよい。
ある態様において、上記の5’末端修飾を有する本発明のminiRNAポリヌクレオチドは、特定された5’末端修飾を有さない類似のコンストラクトと比較した場合に、有意(例えば、少なくとも約25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%またはそれを超えて)により低い「オフ・ターゲット(off-target)」遺伝子サイレンシングを示し、したがって、RNAi試薬または治療の全体的な特異性を著しく改善する。
本発明のこの側面によれば、特定のガイド鎖修飾が、RNAi活性を著しく低下させることなく(またはRNAi活性を全く低下させることなく)、さらにヌクレアーゼ安定性を増大し、および/またはインターフェロン誘導を低下させる。
特定の5’ステム配列の修飾と3’ステム配列の修飾との特定の組み合わせは、標的遺伝子の発現を阻害する能力の増強、血清安定性の増強、および/または標的特異性の増大などにより部分的に表わされる、さらなる予想外の利点をもたらし得る。
ある態様において、修飾RNAiコンストラクトは、同じ配列を有する未修飾RNAiコンストラクトと比較して、改善した血清および/または脳脊髄液中の安定性を有し得る。
ある態様において、RNAiコンストラクトの構造は、ヒト、マウスおよび他のげっ歯類、ならびに他の非ヒト哺乳動物からの初代細胞を含む哺乳動物の初代細胞などの初代細胞において、インターフェロン応答を誘導しない。ある態様において、RNAiコンストラクトはまた、無脊椎生物において標的遺伝子の発現を阻害するために用いることができる。
哺乳動物は、さらに、対象となるRNAiコンストラクトと薬学的に受容可能なキャリアまたは希釈剤とを含む組成物に関する。
方法は、in vitroで、ex vivoで、またはin vivoで、例えば、培養中のヒト細胞などの培養中の哺乳動物細胞において行うことができる。
標的細胞(例えば哺乳動物細胞)は、脂質(例えばカチオン性脂質)またはリポソームなどの送達試薬の存在下において、接触させてもよい。
本発明の別の側面は、哺乳動物細胞において標的遺伝子の発現を阻害するための方法を提供し、該方法は、哺乳動物細胞を、対象となるRNAiコンストラクトを発現するベクターと接触させることを含む。
分子の他方の部分は、一本鎖領域である。一本鎖領域は、7〜40ヌクレオチドの範囲であると予測される。
ガイド鎖(第1のポリヌクレオチド)のRISC複合体中へのローディングの効率は、重度に修飾されたポリヌクレオチドについて変化する場合があるので、本発明の一態様においては、効率的なガイド鎖のローディングを促進するために、デュプレックスポリヌクレオチドは、ガイド鎖(第1のポリヌクレオチド)上のヌクレオチド9、11、12、13または14と、センス鎖(第2のポリヌクレオチド)上の反対のヌクレオチドとの間のミスマッチを含む。
デュプレックスの特徴
本発明の二本鎖オリゴヌクレオチドは、2つの別々の相補的な核酸鎖により形成することができる。デュプレックス形成は、標的遺伝子を含有する細胞の内側で起きても外側で起きてもよい。
本発明のヌクレオチドは、糖部分、ホスホジエステル結合および/または塩基を含む、多様な位置において修飾することができる。
糖部分は、天然の未修飾糖、例えば単糖(ペントース、例えばリボース、デオキシリボースなど)、修飾糖および糖アナログを含む。一般に、可能なヌクレオモノマーの修飾、特に糖部分のものとして、例えば、ヒドロキシル基の1または2以上の、ハロゲン、ヘテロ原子、脂肪族基での置き換え、またはヒドロキシル基の、エーテル、アミン、チオールなどとしての官能化が挙げられる。
アンチセンス(ガイド)鎖は、標的遺伝子の少なくとも一部に対して実質的に同一であり得るが、少なくとも塩基対形成に関連して、配列は、有用であるために、例えば標的遺伝子の表現型の発現を阻害するために、完全に同一である必要はない。一般に、より高い相同性は、より短いアンチセンス遺伝子の使用を埋め合わせるために用いられ得る。一部のケースにおいて、アンチセンス鎖は、一般に、標的遺伝子に対して(アンチセンス方向において)実質的に同一である。
用語「ヒドロキシ」または「ヒドロキシル」は、(適切なカウンターイオンと共に)−OHまたは−O−を有する基を含む。
用語「ハロゲン」は、フッ素、臭素、塩素、ヨウ素などを含む。用語「全ハロゲン化」は、一般に、全ての水素がハロゲン原子により置き換えられている部分を指す。
用語「ヌクレオチド」は、リン酸基またはリン酸アナログをさらに含むヌクレオシドを含む。
ある態様において、ガイド配列を超えるヌクレオチドの殆どまたは全ては(2’修飾されていようがいまいが)ホスホロチオエート結合により結合している。かかるコンストラクトは、その血清タンパク質に対するより高いアフィニティーに起因して、薬物動態学が改善されている傾向がある。ポリヌクレオチドの非ガイド配列部分におけるホスホロチオエート結合は、一般に、一旦ガイド鎖がRISCにロードされた後は、ガイド鎖の活性に干渉しない。
本発明のオリゴヌクレオチドは、当該分野において公知の任意の方法により、例えば、酵素による合成および/または化学合成を用いて、合成することができる。オリゴヌクレオチドは、in vitroで(例えば、酵素による合成および化学合成を用いて)、またはin vivoで(当該分野において周知の組み換えDNA技術を用いて)合成することができる。
細胞によるオリゴヌクレオチドの取り込み
オリゴヌクレオチドおよびオリゴヌクレオチド組成物は、1または2以上の細胞または細胞ライセートと接触させられ(すなわち、接触させられる、または本明細書においては投与または送達されるとして言及される)、これに取り込まれる。用語「細胞」は、原核および真核細胞、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を含む。好ましい態様において、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られる。
カプセル化剤は、ビヒクル中にオリゴヌクレオチドを補足する。本発明の別の態様において、オリゴヌクレオチドは、キャリアまたはビヒクル、例えば、リポソームまたはミセルと結合していてもよいが、他のキャリアを用いることもできることは、当業者により理解される通りである。リポソームは、脂質二重層からなるビヒクルであって、生体膜と類似する構造を有する。かかるキャリアは、細胞による取り込みを促進するため、またはオリゴヌクレオチドを標的化するため、またはオリゴヌクレオチドの薬物動態学または毒性学的特性を改善するために、用いられる。
本発明の目的のために、用語「フィトステロール」(また、植物ステロールとも称される)は、植物において天然に存在する植物化学物質である、一群のステロイドアルコール類である。200種を超える既知のフィトステロールが存在する。
本発明の目的のために、用語「ステロールの側鎖」は、ステロール型分子の17位において結合する側鎖の化学組成を指す。標準的な定義において、ステロールは、8炭素鎖を17位に保有する4環構造に限定される。本発明において、従来のものよりも長いおよび短い側鎖を有するステロール型分子が記載される。側鎖は、分子であっても、二重の骨格を含んでいてもよい。
中性脂質混合物として、天然に存在する、または化学合成された、または修飾された、飽和および不飽和脂肪酸残基のクラスから選択される製剤が挙げられる。脂肪酸は、トリグリセリド、ジグリセリドまたは個々の脂肪酸の形態において存在し得る。別の態様において、薬理学において非経口栄養のために現在用いられている脂肪酸のよく確認された混合物および/または脂質乳液を利用してもよい。
複合体化剤は、強力であるが共有結合ではない引力(例えば、静電気、ファンデルワールス、パイ・スタッキングなどの相互作用)により、本発明のオリゴヌクレオチドに結合する。一態様において、本発明のオリゴヌクレオチドは、オリゴヌクレオチドの細胞による取り込みを増大するために、複合体化剤と複合体化してもよい。複合体化剤の一例として、カチオン性脂質が挙げられる。カチオン性脂質は、オリゴヌクレオチドを細胞へ送達するために用いることができる。しかし、上記のとおり、カチオン性脂質を含まない製剤が、一部の態様において好ましい。
オリゴヌクレオチドの送達はまた、オリゴヌクレオチドを細胞受容体へ標的化することによっても改善し得る。標的化部分は、オリゴヌクレオチドに抱合させても、オリゴヌクレオチドに結合したキャリア基(すなわち、ポリ(L−リジン)またはリポソーム)に結合させてもよい。この方法は、特異的受容体により媒介されるエンドサイトーシスを示す細胞に良好に適する。
オリゴヌクレオチドの最適な投与または送達の経路は、所望の結果および/または処置される対象に依存して変化し得る。本明細書において用いられる場合、「投与」は、細胞をオリゴヌクレオチドに接触させることを指し、in vitroで、またはin vivoで行うことができる。標的核酸分子から翻訳されるタンパク質の発現を最適に減少させるために、オリゴヌクレオチドの投与量を、例えばRNA安定性の読み出しによりまたは治療応答により測定されるものとして、過度の実験なしに調整することができる。
一部の態様において、本発明のオリゴヌクレオチドは、安定であり、すなわち、エンドヌクレアーゼおよびエクソヌクレアーゼ分解に対して実質的に安定である。オリゴヌクレオチドは、それが内因性の細胞ヌクレアーゼによる攻撃に対して少なくとも約3倍耐性が高い場合に、ヌクレアーゼに対して実質的に耐性であるとして、および、それが対応するオリゴヌクレオチドよりも少なくとも約6倍耐性が高い場合に、高度にヌクレアーゼ耐性であるとして、定義される。これは、当該分野において公知である技術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、実証することができる。
遺伝子の発現を阻害することにより、本発明のオリゴヌクレオチド組成物は、タンパク質の発現を伴う任意の疾患を処置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処置することができる疾患の例として、単に説明するために、癌、網膜症、自己免疫疾患、炎症性疾患(すなわち、ICAM-1関連障害、乾癬、潰瘍性大腸炎、クローン病)、ウイルス疾患(すなわち、HIV、C型肝炎)、miRNA障害、および心血管性疾患が挙げられる。
例1:最短トリガーRNAを用いた遺伝子発現の阻害
最短トリガー(Minimum Length Trigger:mlt)RNAのトランスフェクション
mltRNAコンストラクトを、化学合成し(Integrated DNA Technologies, Coralville, IA)、リポフェクタミンRNAiMAX(Invitrogen, Carlsbad, CA)試薬を製造者の指示書に従って用いて、HEK293細胞(ATCC, Manassas, VA)中にトランスフェクトした。簡単に述べると、RNAを12×の濃度に希釈し、次いで、12×の濃度のリポフェクタミンRNAiMAXと組み合わせて複合体とした。RNAおよびトランスフェクション試薬を、室温で20分間複合体化させ、6×の濃度にした。複合体化の間に、HEK293細胞を洗浄し、トリプシン処理し、計数した。細胞を、製造者および先に記載される条件により推奨される濃度まで希釈した。これは1×105細胞/mlであった。RNAとRNAiMAXトランスフェクション試薬との複合体化が完成したら、20ulの複合体を、96ウェルプレートの適切なウェルに、3個に分けて、添加した。細胞を各ウェルに添加し(100ulの容量)、ウェルごとの最終細胞数を1×104細胞/ウェルとした。細胞の容積が、6×の濃度の複合体を、1×まで希釈し、これは、記録される濃度と等しかった(10〜0.05nM)。細胞を24〜48時間、通常の増殖条件下においてインキュベートした。
ΔGは、Mfoldインターネットサイト(http://mfold.bioinfo.rpi.edu/cgi-bin/rna-form1.cgi)を通して利用可能なMfoldを用いて計算した。ΔGを計算するための方法は、以下の参考文献において記載され、これらから本明細書において参考として組み込まれる:Zuker, M. (2003) Nucleic Acids Res., 31(13):3406-15; Mathews, D. H., Sabina, J., Zuker, M. and Turner, D. H. (1999) J. Mol. Biol. 288:911-940; Mathews, D. H., Disney, M. D., Childs, J. L., Schroeder, S. J., Zuker, M., and Turner, D. H. (2004) Proc. Natl. Acad. Sci. 101:7287-7292; Duan, S., Mathews, D. H., and Turner, D. H. (2006) Biochemistry 45:9819-9832; Wuchty, S., Fontana, W., Hofacker, I. L., and Schuster, P. (1999) Biopolymers 49:145-165。
最短二本鎖領域を有する非対称二本鎖RNAi分子を、本明細書において開発した。これは遺伝子サイレンシングにおいて高度に有効である。これらの分子は、センスおよび/またはアンチセンス鎖上に多様な化学修飾を含んでもよく、コレステロールなどのステロール様化合物に抱合してもよい
sd-rxRNAnanoのトランスフェクション
脂質媒介性トランスフェクション
sd-rxRNAnanoコンストラクトを化学合成し(Dharmacon, Lafayette, CO)、リポフェクタミンRNAiMAX(Invitrogen, Carlsbad, CA)を製造者の指示書に従って用いて、HEK293細胞(ATCC, Manassas, VA)中へトランスフェクトした。簡単に述べると、RNAを、Opti-MEM登録商標1 Reduced Serum Media(Invitrogen, Carlsbad, California)中で12×の濃度まで希釈し、次いで、12×の濃度のリポフェクタミンRNAiMAXと組み合わせた。RNAおよびトランスフェクション試薬を、室温で20分間複合体化させ、6×の濃度にした。複合体化の間に、HEK293細胞を洗浄し、トリプシン処理し、計数した。細胞を、製造者および先に記載される条件により推奨される1×105細胞/mlの濃度まで希釈した。RNAとRNAiMAXトランスフェクション試薬との複合体化が完成したら、20ulの複合体を、96ウェルプレートの適切なウェルに、3個に分けて、添加した。細胞を各ウェルに添加し(100ulの容量)、ウェルごとの最終細胞数を1×104細胞/ウェルとした。細胞の容積が、6×の濃度の複合体を、1×まで希釈した(10〜0.05nM)。細胞を24〜48時間、通常の増殖条件下においてインキュベートした。24または48時間のインキュベーションの後で、細胞を溶解し、bDNAハイブリダイゼーション技術を使用するQuantiGeneアッセイ(Panomics, Freemont, CA)を用いて、遺伝子サイレンシング活性を測定した。アッセイを、製造者の指示書に従って行った。
sd-rxRNAnanoコンストラクトを化学合成した(Dharmacon, Lafayette, CO)。トランスフェクションの24時間前に、HeLa細胞(ATCC, Manassas, VA)を、1×104細胞/ウェルで、96ウェルプレートに、通常の増殖条件下において(DMEM、10%のFBS、ならびに1%のペニシリンおよびストレプトマイシン)播種した。HeLa細胞のトランスフェクションの前に、sd-rxRNAnanoを、Accell siRNA送達用培地(Delivery Media)(Dharmacon, Lafayette, CO)中で0.01uM〜1uMの最終濃度まで希釈した。通常の増殖培地を、細胞から吸引除去し、適切な濃度のsd-rxRNAnanoを含む100uLのAccell送達用培地を細胞に適用した。トランスフェクションの48時間後に、送達用培地を細胞から吸引除去して、さらなる24時間にわたり通常の増殖培地を細胞に適用した。
当業者は、慣用的な実験のみを用いて、本明細書において記載される発明の具体的な態様への多数の均等物を理解するか、またはそれに気付くことができる。かかる均等物は、以下の特許請求の範囲により包含されることが意図される。
Claims (91)
- 単離された非対称の核酸分子であって、二本鎖核酸を形成する、16ヌクレオチドの最短の長さを有するガイド鎖およびパッセンジャー鎖を含み、二本鎖領域および一本鎖領域を有し、前記二本鎖領域は8〜15ヌクレオチドの長さを有し、前記一本鎖領域は5〜12ヌクレオチドの長さを有し、ここで、前記パッセンジャー鎖は親油性基に結合しており、ここで、前記二本鎖核酸のヌクレオチドのうち少なくとも40%は修飾されており、およびここで、前記一本鎖領域は、少なくとも2個のホスホロチオエート修飾を有する、前記核酸分子。
- ガイド鎖の1位が、5’リン酸化されている、請求項1に記載の単離された非対称の核酸分子。
- ガイド鎖の1位が、2’O−メチル修飾および5’リン酸化されている、請求項1に記載の単離された非対称の核酸分子。
- 単離された二本鎖核酸分子であって、miRNA配列に対して相補性を有する長さ15〜21ヌクレオチドのより長い鎖と、3’末端において親油性基に結合した長さ8〜16ヌクレオチドのより短い鎖とを含み、ここで、前記より長い鎖および前記パッセンジャー鎖が二本鎖領域および一本鎖領域を有する二本鎖核酸分子を形成し、ここで、より長い鎖は、長さ2〜13ヌクレオチドの3’一本鎖領域を有し、少なくとも2個のホスホロチオエート修飾を含み、少なくとも50%のヌクレオチドが修飾されている、前記二本鎖核酸分子。
- 単離された二本鎖核酸分子であって、
標的遺伝子に対して相補性を有する長さ17〜21ヌクレオチドのガイド鎖、
3’末端において親油性基に結合した長さ8〜16ヌクレオチドのパッセンジャー鎖
を含み、
ここで、前記ガイド鎖および前記パッセンジャー鎖が、二本鎖領域および一本鎖領域を有する二本鎖核酸分子を形成し、ここで、前記ガイド鎖は、長さ2〜13ヌクレオチドの3’一本鎖領域を有し、前記一本鎖領域内の各々のヌクレオチドは、ホスホロチオエート修飾を有し、ここで、前記ガイド鎖は5’リン酸修飾を有し、およびここで、前記二本鎖領域中のCおよびUヌクレオチドのうち少なくとも50%は、少なくとも1つの2’O−メチル修飾または2’−フルオロ修飾を含む、前記二本鎖核酸分子。 - 単離された二本鎖核酸分子であって、
標的遺伝子に対して相補性を有する長さ17〜21ヌクレオチドのガイド鎖、
3’末端において親油性基に結合した長さ10〜16ヌクレオチドのパッセンジャー鎖
を含み、
ここで、前記ガイド鎖および前記パッセンジャー鎖が、二本鎖領域および一本鎖領域を有する二本鎖核酸分子を形成し、ここで、前記ガイド鎖は、長さ5〜11ヌクレオチドの3’一本鎖領域を有し、前記一本鎖領域内の少なくとも2個のヌクレオチドは、ホスホロチオエート修飾を有し、ここで、前記ガイド鎖は5’リン酸修飾を有し、およびここで、前記二本鎖領域中のCおよびUヌクレオチドのうち少なくとも50%は、2’O−メチル修飾または2’−フルオロ修飾されている、前記二本鎖核酸分子。 - 単離された二本鎖核酸分子であって、
標的遺伝子に対して相補性を有する長さ17〜21ヌクレオチドのガイド鎖、
3’末端において親油性基に結合した長さ8〜16ヌクレオチドのパッセンジャー鎖
を含み、
ここで、前記ガイド鎖および前記パッセンジャー鎖が、二本鎖領域および一本鎖領域を有する二本鎖核酸分子を形成し、ここで、前記ガイド鎖は、長さ6〜8ヌクレオチドの3’一本鎖領域を有し、前記一本鎖領域内の各々のヌクレオチドは、ホスホロチオエート修飾を有し、ここで、前記ガイド鎖は5’リン酸修飾を有し、ここで、前記パッセンジャー鎖は、少なくとも2個のホスホロチオエート修飾を含み、ここで、前記二本鎖領域中のCおよびUヌクレオチドのうち少なくとも50%は、2’O−メチル修飾または2’−フルオロ修飾を含み、およびここで、前記二本鎖核酸分子は、平滑であるかまたは1〜2ヌクレオチドの突出を含む1つの末端を有する、前記二本鎖核酸分子。 - 単離された二本鎖核酸分子であって、
標的遺伝子に対して相補性を有する長さ17〜21ヌクレオチドのガイド鎖、
3’末端において親油性基に結合した長さ8〜16ヌクレオチドのパッセンジャー鎖
を含み、
ここで、前記ガイド鎖および前記パッセンジャー鎖が、二本鎖領域および一本鎖領域を有する二本鎖核酸分子を形成し、ここで、前記ガイド鎖は、3’一本鎖領域を有し、前記一本鎖領域内の各々のヌクレオチドは、ホスホロチオエート修飾を有し、ここで、前記ガイド鎖は5’リン酸修飾を有し、ここで、前記ガイド鎖の11〜18位中の全てのCおよびUヌクレオチドは、2’O−メチル修飾を有し、ここで、前記パッセンジャー鎖中の全てのヌクレオチドは、2’O−メチル修飾されており、およびここで、前記二本鎖核酸分子は、平滑であるかまたは1〜2ヌクレオチドの突出を含む1つの末端を有する、前記二本鎖核酸分子。 - 単離された二本鎖核酸分子であって、
標的遺伝子に対して相補性を有する長さ17〜21ヌクレオチドのガイド鎖、
3’末端において親油性基に結合した長さ8〜15ヌクレオチドのパッセンジャー鎖
を含み、ここで、前記親油性基は、コレステロールおよび長さ5〜7または9〜18個の炭素のC17ポリ炭素鎖を有するステロール型分子からなる群より選択され、
ここで、前記ガイド鎖および前記パッセンジャー鎖が、二本鎖領域および一本鎖領域を有する二本鎖核酸分子を形成し、ここで、前記ガイド鎖は、3’一本鎖領域を有し、前記一本鎖領域内の各々のヌクレオチドは、ホスホロチオエート修飾を有し、ここで、前記ガイド鎖は5’リン酸修飾を有し、ここで、前記ガイド鎖の11〜18位中の全てのCおよびUヌクレオチドは、2’O−メチル修飾を有し、ここで、ガイド鎖の2〜10位中の全てのCおよびUヌクレオチドは、2’F修飾を有し、ここで、前記パッセンジャー鎖中の全てのヌクレオチドは、2’O−メチル修飾されており、およびここで、前記二本鎖核酸分子は、平滑であるかまたは1〜2ヌクレオチドの突出を含む1つの末端を有する、前記二本鎖核酸分子。 - 単離された核酸分子であって、
標的遺伝子に対して相補性を有するガイド配列、
3’末端において親油性基に結合したパッセンジャー配列
を含み、
ここで、前記ガイド配列および前記パッセンジャー配列が、二本鎖領域および一本鎖領域を有する核酸分子を形成し、ここで、前記ガイド配列は、長さ2〜13ヌクレオチドの3’一本鎖領域を有し、前記一本鎖領域内の各々のヌクレオチドは、ホスホロチオエート修飾を有し、ここで、前記ガイド配列は、5’リン酸修飾を有し、ここで、前記二本鎖領域中のCおよびUヌクレオチドのうち少なくとも50%は、少なくとも1つの2’O−メチル修飾または2’−フルオロ修飾を含み、およびここで、前記二本鎖核酸分子は、平滑であるかまたは1〜2ヌクレオチドの突出を含む1つの末端を有する、前記核酸分子。 - ガイド鎖およびパッセンジャー鎖を含む単離された二本鎖核酸分子であって、ここで、前記分子の二本鎖である領域は、8〜14ヌクレオチド長であり、ここで、前記ガイド鎖は、4〜12ヌクレオチド長である一本鎖領域を含み、およびここで、前記ガイド鎖の一本鎖領域は、2〜12個のホスホロチオエート修飾を含む、前記二本鎖核酸分子。
- ガイド鎖が、6〜8個のホスホロチオエート修飾を含む、請求項11に記載の核酸分子。
- ガイド鎖の一本鎖領域が、6ヌクレオチド長である、請求項11または12に記載の核酸分子。
- 二本鎖領域が、13ヌクレオチド長である、請求項11〜13のいずれか一項に記載の核酸分子。
- 二本鎖核酸分子が、平滑であるかまたは1〜2ヌクレオチドの突出を含む1つの末端を有する、請求項11〜14のいずれか一項に記載の核酸分子。
- 単離された二本鎖核酸分子であって、
ガイド鎖、ここで、前記ガイド鎖は、16〜28ヌクレオチド長であり、標的遺伝子に対して相補性を有し、ここで、前記ガイド鎖の3’末端の10ヌクレオチドは、少なくとも2個のリン酸修飾を含み、およびここで、前記ガイド鎖は5’リン酸修飾を有し、少なくとも1つの2’O−メチル修飾または2’−フルオロ修飾を含む、ならびに
パッセンジャー鎖、ここで、前記パッセンジャー鎖は、8〜14ヌクレオチド長であって、前記ガイド鎖に対する相補性を有し、ここで、前記パッセンジャー鎖は親油性基に結合している、
を含み、
ここで、前記ガイド鎖および前記パッセンジャー鎖が、前記二本鎖核酸分子を形成する、前記二本鎖核酸分子。 - 前記ガイド鎖または配列の1位におけるヌクレオチドが、2’−O−メチル修飾を有する、請求項1、7〜10または16のいずれか一項に記載の核酸分子。
- ガイド鎖または配列の2〜10位における少なくとも1つのCまたはUヌクレオチドが、2’−フルオロ修飾を有する、請求項1〜4、6〜10または16〜17のいずれか一項に記載の核酸分子。
- ガイド鎖または配列の2〜10位における全てのCおよびUヌクレオチドが、2’−フルオロ修飾を有する、請求項18に記載の核酸分子。
- ガイド鎖または配列の11〜18位における少なくとも1つのCまたはUヌクレオチドが、2’−O−メチル修飾を有する請求項1〜3、5、7、9または16〜19のいずれか一項に記載の核酸分子。
- ガイド鎖または配列の11〜18位における全てのCおよびUヌクレオチドが、2’−O−メチル修飾を有する、請求項20に記載の核酸分子。
- ガイド鎖の3’末端の10ヌクレオチドが、少なくとも4個のリン酸修飾を含む、請求項1、2、4、5または16〜21のいずれか一項に記載の核酸分子。
- ガイド鎖の3’末端の10ヌクレオチドが、少なくとも8個のリン酸修飾を含む、請求項22に記載の核酸分子。
- ガイド鎖が、4〜14個のリン酸修飾を含む、請求項16に記載の核酸分子。
- ガイド鎖が、4〜10個のリン酸修飾を含む、請求項16に記載の核酸分子。
- ガイド鎖の3’末端の6ヌクレオチドが、全てリン酸修飾を含む、請求項1〜5または16のいずれか一項に記載の核酸分子。
- リン酸修飾が、ホスホロチオエート修飾である、請求項16〜26のいずれか一項に記載の核酸分子。
- パッセンジャー鎖上の全てのCおよびUヌクレオチドが、2’−O−メチル修飾を有する、請求項16〜27のいずれか一項に記載の核酸分子。
- パッセンジャー鎖上の全てのヌクレオチドが、2’−O−メチル修飾を有する、請求項28に記載の核酸分子。
- パッセンジャー鎖上の少なくとも1個のヌクレオチドが、ホスホロチオエート修飾されている、請求項16〜30のいずれか一項に記載の核酸分子。
- パッセンジャー鎖上の少なくとも2個のヌクレオチドが、ホスホロチオエート修飾されている、請求項30に記載の核酸分子。
- 親油性分子が、ステロールである、請求項1〜5または16〜31のいずれか一項に記載の核酸分子。
- ステロールが、コレステロールである、請求項32に記載の核酸分子。
- ガイド鎖が、18〜19ヌクレオチド長である、請求項16〜33のいずれか一項に記載の核酸分子。
- パッセンジャー鎖が、11〜13ヌクレオチド長である、請求項16〜34のいずれか一項に記載の核酸分子。
- 前記二本鎖核酸分子が、平滑であるかまたは1〜2ヌクレオチドの突出を含む1つの末端を有する、請求項16〜35のいずれか一項に記載の核酸分子。
- ガイド鎖およびパッセンジャー鎖を含む単離された二本鎖核酸分子であって、ここで、前記ガイド鎖は16〜29ヌクレオチド長であって、標的遺伝子に対して実質的に相補性であり、ここで、前記パッセンジャー鎖は、8〜14ヌクレオチド長であって、前記ガイド鎖に対して相補性を有し、およびここで、前記ガイド鎖は、少なくとも2個の化学修飾を有する、前記二本鎖核酸分子。
- 少なくとも2個の化学修飾が、少なくとも2個のホスホロチオエート修飾を含む、請求項37に記載の単離された二本鎖核酸分子。
- 二本鎖核酸分子が、平滑であるかまたは1〜2ヌクレオチドの突出を含む1つの末端を有する、請求項37〜38のいずれか一項に記載の核酸分子。
- ガイド鎖およびパッセンジャー鎖を含む単離された二本鎖核酸分子であって、ここで、前記ガイド鎖は、16〜29ヌクレオチド長であって、標的遺伝子に対して実質的に相補性であり、ここで、前記パッセンジャー鎖は、8〜14ヌクレオチド長であって、前記ガイド鎖に対して相補性を有し、およびここで、前記ガイド鎖は、5ヌクレオチドまたはそれより長い一本鎖3’領域および1ヌクレオチドまたはそれより短い5’領域を有する、前記二本鎖核酸分子。
- 一本鎖領域が、少なくとも2個のホスホロチオエート修飾を含む、請求項40に記載の核酸分子。
- ガイド鎖およびパッセンジャー鎖を含む単離された二本鎖核酸分子であって、ここで、前記ガイド鎖は、16〜29ヌクレオチド長であって、標的遺伝子に対して実質的に相補性であり、ここで、前記パッセンジャー鎖は、8〜16ヌクレオチド長であって、前記ガイド鎖に対して相補性を有し、およびここで、前記ガイド鎖は、5ヌクレオチドまたはそれより長い一本鎖3’領域を有し、パッセンジャー鎖は、9より長いC17の付加された鎖を有するステロール型分子を有する、前記二本鎖核酸分子。
- デュプレックスポリヌクレオチドであって、
第1のポリヌクレオチド、ここで、前記第1のポリヌクレオチドは、第2のポリヌクレオチドおよび標的遺伝子に対して相補的である;ならびに
第2のポリヌクレオチド、ここで前記第2のポリヌクレオチドは、前記第1のポリヌクレオチドよりも少なくとも6ヌクレオチド短い、
を含み、
ここで、前記第1のポリヌクレオチドは、40〜90%の疎水性塩基修飾、40〜90%のホスホロチオエートおよび40〜90%のリボース部分の修飾または任意のこれらの組み合わせからなる群より選択される修飾を含む一本鎖領域を含む、前記デュプレックスポリヌクレオチド。 - デュプレックスポリヌクレオチドであって、
第1のポリヌクレオチド、ここで、前記第1のポリヌクレオチドは、第2のポリヌクレオチドおよび標的遺伝子に対して相補的である;ならびに
第2のポリヌクレオチド、ここで、前記第2のポリヌクレオチドは、前記第1のポリヌクレオチドよりも少なくとも6ヌクレオチド短い、
を含み、
ここで、前記デュプレックスポリヌクレオチドは、前記第1のポリヌクレオチド上のヌクレオチド9、11、12、13または14と、前記第2のポリヌクレオチド上の反対のヌクレオチドとの間にミスマッチを含む、前記デュプレックスポリヌクレオチド。 - 哺乳動物細胞において標的遺伝子の発現を阻害するための方法であって、哺乳動物細胞を、請求項1〜41のいずれか一項に記載の単離された二本鎖核酸分子または請求項43もしくは44に記載のデュプレックスポリヌクレオチドと接触させることを含む、前記方法。
- 対象においてRNAiを誘導する方法であって、
対象に、請求項1〜41のいずれか一項に記載の単離された二本鎖核酸分子または請求項43もしくは44に記載のデュプレックスポリヌクレオチドの、標的遺伝子のmRNAのRNAiを誘導するための有効量を投与すること
を含む、前記方法。 - 対象が、ヒトである、請求項46に記載の方法。
- 標的遺伝子が、PPIBである、請求項45に記載の方法。
- 標的遺伝子が、MAP4K4である、請求項45に記載の方法。
- 標的遺伝子が、SOD1である、請求項45に記載の方法。
- 単離された疎水性修飾ポリヌクレオチドであって、
ポリヌクレオチド、ここで、前記ポリヌクレオチドは二本鎖RNAであって、疎水性分子に結合し、ここで、前記疎水性分子は、非末端のヌクレオチドの塩基、リボースまたは骨格に結合し、およびここで、前記単離された二本鎖核酸分子は、ガイド鎖およびパッセンジャー鎖を含み、ここで、前記ガイド鎖は16〜29ヌクレオチド長であって、標的遺伝子に対して実質的に相補性であり、ここで、前記パッセンジャー鎖は、8〜14ヌクレオチド長であって、前記ガイド鎖に対して相補性を有する、
を含む、前記疎水性修飾ポリヌクレオチド。 - 疎水性分子が、二本鎖RNAのガイド鎖に結合している、請求項51に記載の単離された疎水性修飾ポリヌクレオチド。
- 請求項51に記載の単離された疎水性修飾ポリヌクレオチドであって、ここで、前記ガイド鎖の3’末端の10ヌクレオチドは、少なくとも2個のリン酸修飾を含み、およびここで、前記ガイド鎖は5’リン酸修飾を有し、少なくとも1つの2’O−メチル修飾または2’−フルオロ修飾を含む、前記疎水性修飾ポリヌクレオチド。
- 疎水性分子が、二本鎖RNAのパッセンジャー鎖に結合している、請求項51に記載の単離された疎水性修飾ポリヌクレオチド。
- 単離された疎水性修飾ポリヌクレオチドであって、
非共有結合的に疎水性分子と複合体化したポリヌクレオチド、ここで、前記疎水性分子は、ポリカチオン性分子である、
を含む、前記疎水性修飾ポリヌクレオチド。 - ポリカチオン性分子が、プロタミン、アルギニンリッチペプチドおよびスペルミンからなる群より選択される、請求項55に記載の単離された疎水性修飾ポリヌクレオチド。
- 単離された疎水性修飾ポリヌクレオチドであって、
ポリヌクレオチド、ここで、前記ポリヌクレオチドは二本鎖RNAであって、疎水性分子にリンカーなしで直接的に複合体化し、ここで、疎水性分子はコレステロールではない。
を含む、前記疎水性修飾ポリヌクレオチド。 - 組成物であって、以下:
疎水性修飾ポリヌクレオチド、ここで、前記ポリヌクレオチドは二本鎖RNAであって、疎水性分子に結合し、ここで、前記二本鎖核酸分子は、ガイド鎖およびパッセンジャー鎖を含み、ここで、前記ガイド鎖は16〜29ヌクレオチド長であって、標的遺伝子に対して実質的に相補性であり、ここで、前記パッセンジャー鎖は、8〜14ヌクレオチド長であって、前記ガイド鎖に対して相補性を有し、ここで、ガイド鎖の1位は、5’リン酸化されているかまたは2’O−メチル修飾を有し、ここで、前記二本鎖核酸のヌクレオチドのうち少なくとも40%は修飾されており、およびここで、前記二本鎖核酸分子は、平滑であるか、または1〜2ヌクレオチドの突出を含む一つの末端を有する;
中性脂質混合物;ならびに
任意に、カーゴ分子、
を含み、
ここで、前記疎水性修飾ポリヌクレオチドと前記中性脂質混合物は、ミセルを形成する、前記組成物。 - パッセンジャー鎖の3’末端が、疎水性分子に結合している、請求項58に記載の組成物。
- 組成物が、無菌である、請求項58〜60のいずれか一項に記載の組成物。
- 中性脂質混合物が、DOPC(ジオレオイルホスファチジルコリン)を含む、請求項58〜60のいずれか一項に記載の組成物。
- 中性脂質混合物がDSPC(ジステアロイルホスファチジルコリン)を含む、請求項58〜60のいずれか一項に記載の組成物。
- 中性脂質混合物が、さらにコレステロールを含む、請求項58〜62のいずれか一項に記載の組成物。
- ステロールが、コレステロールである、請求項62に記載の組成物。.
- 少なくとも20%のDOPCおよび少なくとも20%のコレステロールを含む、請求項57〜55のいずれか一項に記載の組成物。
- 疎水性修飾ポリヌクレオチドの疎水性部分が、ステロールである、請求項57〜64のいずれか一項に記載の組成物。
- ステロールが、コレステロール、コレステリルまたは修飾コレステリル残基である、請求項65に記載の組成物。
- 疎水性修飾ポリヌクレオチドの疎水性部分が、胆汁酸、コール酸またはタウロコール酸、デオキシコール酸、オレイルリトコール酸、オレオイルコレン酸、糖脂質、リン脂質、スフィンゴ脂質、イソプレノイド類、ビタミン類、飽和脂肪酸、不飽和脂肪酸、脂肪酸エステル類、トリグリセリド、ピレン類、ポルフィリン類、テキサフィリン、アダマンタン、アクリジン類、ビオチン、クマリン、フルオレセイン、ローダミン、Texas-Red、ジゴキシゲニン、ジメトキシトリチル、t−ブチルジメチルシリル、t−ブチルジフェニルシリル、シアニン色素(例えば、Cy3またはCy5)、Hoechst 33258色素、ソラレン、またはイブプロフェンからなる群より選択される、請求項57〜64のいずれか一項に記載の組成物。
- 疎水性修飾ポリヌクレオチドの疎水性部分がポリカチオン性分子である、請求項57〜64または67のいずれか一項に記載の組成物。
- ポリカチオン性分子が、プロタミン、アルギニンリッチペプチドおよびスペルミンからなる群より選択される、請求項18に記載の組成物。
- カーゴ分子が、脂質、ペプチド、ビタミン、または小分子である、請求項57〜69のいずれか一項に記載の組成物。
- カーゴ分子が、非経口栄養からなる群より選択される多様な目的のために利用可能な市販の脂質乳液である、請求項57〜69のいずれか一項に記載の組成物。
- 市販の脂質乳液が、イントラリピッド(intralipid)またはニュートラリピッド(nutralipid)である、請求項71に記載の組成物。
- カーゴ分子が、74%を超えるリノール酸を含む脂肪酸混合物である、請求項57〜69のいずれか一項に記載の組成物。
- カーゴ分子が、少なくとも6%のカルジオリピンを含む脂肪酸混合物である、請求項57〜69のいずれか一項に記載の組成物。
- カーゴ分子が、少なくとも74%のリノール酸および少なくとも6%のカルジオリピンを含む脂肪酸混合物である、請求項57〜69のいずれか一項に記載の組成物。
- ポリヌクレオチドのヌクレオチドのうちの少なくとも40%が修飾されている、請求項57〜75のいずれか一項に記載の組成物。
- カーゴ分子が、膜融合性脂質であり、好ましくは少なくとも10%の膜融合性脂質である、請求項57〜69のいずれか一項に記載の組成物。
- 膜融合性脂質が、DOPEである、請求項77に記載の組成物。
- 対象においてRNAiを誘導する方法であって、
対象に、請求項1〜41のいずれか一項に記載の単離された二本鎖核酸分子、または請求項43もしくは44に記載のデュプレックスポリヌクレオチド、または請求項57〜78のいずれか一項に記載の組成物の、標的遺伝子のmRNAのRNAiを誘導するための有効量を投与すること
を含み、
ここで、前記ポリヌクレオチドは、少なくとも、前記標的遺伝子に対応する配列の領域を有し、ここで、投与の工程は、全身、静脈内、腹腔内、皮内、局所、鼻内、吸入、経口、粘膜内、局所注射、皮下、経口、気管または眼内である、前記方法。 - 投与が、全身である、請求項79に記載の方法。
- 投与が、静脈内である、請求項79に記載の方法。
- 投与が、腹腔内である、請求項79に記載の方法。
- 投与が、皮内である、請求項79に記載の方法。
- 投与が、局所である、請求項79に記載の方法。
- 投与が、眼内である、請求項79に記載の方法。
- 対象が、ヒトである、請求項79に記載の方法。
- 標的遺伝子が、PPIBである、請求項79に記載の方法。
- 標的遺伝子が、MAP4K4である、請求項79に記載の方法。
- 標的遺伝子が、SOD1である、請求項79に記載の方法。
- 単離された二本鎖核酸分子であって、
標的遺伝子に対して相補性を有する長さ17〜21ヌクレオチドのガイド鎖、
3’末端において親油性基に結合した長さ10〜17ヌクレオチドのパッセンジャー鎖、
を含み、
ここで、前記ガイド鎖および前記パッセンジャー鎖が、二本鎖領域および一本鎖領域を有する二本鎖核酸分子を形成し、ここで、前記ガイド鎖は、長さ5〜11ヌクレオチドの3’一本鎖領域を有し、前記一本鎖領域内の少なくとも2個のヌクレオチドは、ホスホロチオエート修飾を有し、ここで、前記ガイド鎖は5’リン酸修飾を有し、およびここで、前記二本鎖領域中のCおよびUヌクレオチドのうち少なくとも50%は、2’O−メチル修飾または2’−フルオロ修飾されている、前記二本鎖核酸分子。
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