JP5805088B2 - 遺伝子発現を阻害する組成物およびその使用 - Google Patents
遺伝子発現を阻害する組成物およびその使用 Download PDFInfo
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- JP5805088B2 JP5805088B2 JP2012526977A JP2012526977A JP5805088B2 JP 5805088 B2 JP5805088 B2 JP 5805088B2 JP 2012526977 A JP2012526977 A JP 2012526977A JP 2012526977 A JP2012526977 A JP 2012526977A JP 5805088 B2 JP5805088 B2 JP 5805088B2
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Description
本発明は、遺伝子発現および/または活性を阻害するための、または、遺伝子発現および/または活性の阻害に応答する疾患および/または病態を診断する、処置する、および/または予防するための、化合物、組成物、および使用方法に関する。
遺伝子発現を阻害するための1つのアプローチは、アンチセンス技術またはRNA阻害(RNAi)である。これらのアプローチは、DNAおよび/またはRNAベースのオリゴヌクレオチドの、選択されたmRNA、マイクロRNA,プレRNA、またはミトコンドリアRNA標的に対する配列特異的結合および、これから生じる翻訳の阻害を利用する。翻訳および最終的に遺伝子発現の、このオリゴヌクレオチドに基づく阻害は、1または2以上の細胞機構の結果であり、これには限定されないが、(i)翻訳の直接的(立体的)妨害、(ii)RNaseH媒介性阻害、および(iii)RNAi媒介性阻害(例えば低分子干渉RNA(siRNA)、マイクロRNA(miRNA)、DNA依存性RNAi(ddRNAi)、および一本鎖RNAi(ssRNAi))を含み得る。
本発明は、新規なアンチセンスオリゴヌクレオチドの、遺伝子発現を下方制御するための治療的および予防的使用に関する。かかる分子は、例えば遺伝子発現を調節するための組成物の提供において、または、患者、対象、動物もしくは生物における遺伝子発現の調節に応答可能な疾患および/または病態を処置するか、および/または予防することにおいて、有用である。
オリゴヌクレオチドベースの化合物の調製
本発明のオリゴヌクレオチドベースの化合物を、DNA/RNA自動合成機でホスホルアミダイト化学を用いて、化学的に合成した。TAC保護(Uを除く)2’−O−TBDMS RNAモノマー、A、G、CおよびUは、Sigma-Aldrichより購入した。7−デアザ−G、イノシンおよびロキソリビンモノマーは、ChemGenes Corporationより購入した。0.25Mの5−エチルチオ−1H−テトラゾール、PCA−無水Cap AおよびCap Bは、Glen Researchより購入した。ジクロロメタン(DCM)中の3%トリクロロ酢酸(TCA)および5%3H−1,2−ベンゾジチオール−3−オン−1,1−ジオキシド(ビューケージ(Beaucage)試薬)は自家で作製した。
本発明のオリゴヌクレオチドベースの化合物を固体支持体から切断し、溶液をさらに65℃に加熱して、エキソ環式アミンの保護基を除去した。得られた溶液は、SpeedVacで完全に乾燥した。
本発明のオリゴヌクレオチドベースの化合物を、イオン交換HPLCで精製した。
カラム:Dionex DNAPac 100カラム(22X250)
カラムヒーター:Chrom Tech TL-105HPLCカラムヒーター、温度は80℃に設定。
バッファーA:20mMのトリス−HCl、pH7.0、20%アセトニトリル。
バッファーB:3.0MのNaCl、20mMのトリス−HCl、pH7.0、20%アセトニトリル
流量:10ml/分
勾配:
0〜2分:0%B
2〜11分:0%Bから35%B
11〜41分:35%Bから90%B
41〜45分:100%B
Watersから購入したCC-18 Sep-Pakカートリッジを、初めに10mlのアセトニトリルで、次に10mlの0.5M酢酸ナトリウムで調整した。10mlの本発明のオリゴヌクレオチドベースの化合物の溶液を負荷した。次に15mlの水を用いて塩を洗い流した。本発明のオリゴヌクレオチドベースの化合物を、水中の1mlの50%アセトニトリルにより溶出した。
本発明のオリゴヌクレオチドベースの化合物を、次の条件に従ってキャピラリー電気泳動で分析した。
機器:Beckman 5010
毛細管:62cmssDNA毛細管
試料の調製:0.2ODの本発明のオリゴヌクレオチドベースの組成物を200ulのRNAse非含有水に溶解した。
注入:5KVで5秒間の動電学的注入
走行条件:14KV、30℃で50分間
本発明のオリゴヌクレオチドベースの化合物を、次の条件に従ってイオン交換HPLCで分析した。
カラム:Dionex DNAPac ガードカラム(22X250)
カラムヒーター:Chrom Tech TL-105HPLCカラムヒーター、温度は80℃に設定。
バッファーA:100mMのトリス−HCl、pH8.0、20%アセトニトリル。
バッファーB:2.0MのLiCl、100mMのトリス−HCl、pH8.0、20%アセトニトリル
流量:2ml/分
勾配:
0〜2分:0%B
2〜10分:0%Bから100%B
10〜15分:100%B
0.3ODの本発明のオリゴヌクレオチドベースの化合物を20%ポリアクリルアミドゲルに負荷し、これを4ワットの定常電力で約5時間走行させた。ゲルは短波長UV光のもとで観察した。
ヒトPBMCの単離
新しく採取した健康なボランティアの血液(CBR Laboratories, Boston, MA)からの末梢血単核細胞(PBMC)を、Ficoll密度勾配遠心法(Histopaque-1077, Sigma)により単離した。
ヒト形質細胞様樹状細胞(pDC)を、新しく得た健康なヒトボランティアの血液PBMCから、製造業者の指示に従ってBDCA4細胞単離キット(Miltenyi Biotec)を用いて正の選択により単離した。
ヒトPBMCを、5×106細胞/mlを用いて48ウェルプレートにプレートした。ヒトpDCを、1×106細胞/mlを用いて96ウェルディッシュにプレートした。例示の本発明のオリゴヌクレオチドベースの化合物をDPBS(pH7.4;Mediatech)に溶解し、これを細胞培養物に0、0.01、1.0または10.0μg/mlの用量で加えた。細胞を次に37℃で24時間インキュベートし、続いて10μg/mlのTLR9アゴニストで24時間刺激した。処理および刺激の後、上清をluminex多重またはELISAアッセイ用に収集した。一定の実験においては、IFN−α、IL−6、および/またはIL−12のレベルをサンドイッチELISAにより測定した。サイトカイン抗体および標準を含む必要な試薬は、PharMingenより購入した。
ヒトB細胞を、PBMCから、CD19細胞単離キット(Miltenyi Biotec, Auburn, CA)を用い製造業者の指示に従って、正の選択により単離した。
マウスTLR9またはTLR7を安定に発現するHEK293細胞(Invivogen, San Diego, CA)を、5%CO2インキュベータにおいて、48ウェルプレート内の、10%熱不活性化FBSを補足した250μL/ウェルのDMEM中にプレートした。80%の集密度において、培養物を一時的に、培養培地中4μL/mLのリポフェクタミン(Invitrogen, Carlsbad, CA)の存在下、ヒト胎児アルカリホスファターゼ(SEAP)レポータープラスミド(pNifty2-Seap)(Invivogen)の分泌形態400ng/mlを用いてトランスフェクトした。プラスミドDNAおよびリポフェクタミンを、無血清培地中で別々に希釈し、室温で5分間インキュベートした。インキュベーション後、希釈したDNAおよびリポフェクタミンを混合し、混合物をさらに室温で20分インキュベートした。100ngのプラスミドDNAおよび1μLのリポフェクタミンを含む、DNA/リポフェクタミン混合物の25μLのアリコートを、細胞培養プレートの各ウェルに加え、細胞を6時間トランスフェクトした。トランスフェクションの後、培地を新鮮な培養培地(抗生物質なし)に置き換えて、0、0.01、1または10μg/mlの、TLR9またはTLR7特異的な本発明のオリゴヌクレオチドベースの化合物をウェルに加え、インキュベーションを24時間継続した。アンチセンス処理に続いて、細胞を次に10μg/mlのTLR9またはTLR7アゴニストで24時間刺激した。
本発明のアンチセンスオリゴヌクレオチドの、TLR7またはTLR8またはその他の特異的RNA標的を阻害する活性を決定するために、次の手順に従った:マウスTLR7またはTLR8またはその他の特異的RNA標的を安定に発現するHEK293細胞(Invivogen, San Diego, CA)を、5%CO2インキュベータにおいて、48ウェルプレート内の、10%熱不活性化FBSを補足した250μL/ウェルのDMEM中にプレートした。80%の集密度において、培養物を一時的に、培養培地中4μL/mLのリポフェクタミン(Invitrogen, Carlsbad, CA)の存在下、ヒト胎児アルカリホスファターゼ(SEAP)レポータープラスミド(pNifty2-Seap)(Invivogen)の分泌形態400ng/mlを用いてトランスフェクトした。プラスミドDNAおよびリポフェクタミンを、無血清培地中で別々に希釈し、室温で5分間インキュベートした。インキュベーション後、希釈DNAおよびリポフェクタミンを混合し、混合物をさらに室温で20分インキュベートした。100ngのプラスミドDNAおよび1μLのリポフェクタミンを含む、DNA/リポフェクタミン混合物の25μLのアリコートを、細胞培養プレートの各ウェルに加え、細胞を6時間トランスフェクトした。トランスフェクションの後、培地を新鮮な培養培地(抗生物質なし)に置き換えて、0、0.01、1または10μg/mlの、本発明の特異的アンチセンスオリゴヌクレオチドをウェルに加え、インキュベーションを24時間継続した。アンチセンス処理に続いて、細胞を次に10μg/mlの標的のアゴニストで24時間まで刺激した。
マウスJ774マクロファージ細胞(American Type Culture Collection, Rockville, MD)を、10%(v/v)ウシ胎仔血清および抗生物質(100IU/mlのペニシリンG/100μg/mlのストレプトマイシン)を補足したダルベッコ修飾イーグル培地で培養した。J774細胞を、6ウェルプレートに5×106細胞/ウェルの密度でプレートした。用量依存性実験のために、J774細胞を次に、0、1、10、50または100μg/mlの本発明のTLR9特異的オリゴヌクレオチドベースの化合物で処理し、インキュベーションを24時間継続した。mRNAへの効果を決定する実験のために、J774細胞を次に、0、1、または3μg/mlの本発明のTLR9特異的オリゴヌクレオチドベースの化合物または対照オリゴヌクレオチドで処理し、インキュベーションを48時間継続した。タンパク質への効果を決定する実験のために、J774細胞を次に、0または50μg/mlの本発明のTLR9特異的オリゴヌクレオチドベースの化合物または対照オリゴヌクレオチドで処理し、インキュベーションを48時間継続した。アンチセンス処理に続いて、細胞抽出物を調製し、TLR9mRNAまたはTLR9タンパク質の量について分析した。
5×106のHeLa細胞(ATCC, Manassas, VA)を、12ウェル培養プレート内の10%ウシ胎仔血清(FBS, Mediatech, Manassas, VA)を補足したダルベッコ修飾イーグル培地(DMEM, Mediatech, Manassas, VA)にプレートした。細胞トランスフェクションには、5μlのリポフェクタミン(登録商標)2000(Invitrogen, Carlsbad, CA)および5μgのアンチセンスオリゴヌクレオチドを、100μlの無血清DMEM中に混合し、室温で15分間インキュベートした。細胞を無血清DMEMで1回洗浄し、100μlのリポフェクタミン/オリゴヌクレオチド複合体を900μlの無血清DMEMに加え、続いて5%CO2を用いて37℃で2時間インキュベーションした。リポフェクタミンのみの群は対照として用いる。培地を次に、10%FBSを加えたDMEMに変更し、24時間インキュベートした。24時間のインキュベーションの後、全RNAを、製造業者の指示に従ってQIAGEN RNeasyミニキット(QIAGEN, Valencia, CA)を用いて単離した。1μgのRNAを用いて、製造業者の推奨に従ってHigh Capacity cDNA Reverse Transcriptionキット(Applied biosystems, Carlsbad, CA)を用いてcDNAの逆転写を行った。定量的リアルタイムPCR(qPCR)には、VEGF用(カタログNO.Hs00900057_ml)およびGAPDH用(Hs99999905_ml)のプライマーおよびプローブを、Applied Biosystemsから購入した。50ngのcDNAを、qPCRにおいてTaqman(登録商標)Fast Universal PCR Master Mix(Applied Biosystems)と共に用いて、反応はApplied BiosystemsのStepOnePlus? Real-Time PCR Systemで製造業者の指示に従って実施した。データを図8Dに、ΔΔCT法を用いて、リポフェクタミン処理細胞に対する相対的なmRNAの量として示し、ここで、ΔCT=CTVEGF−CTGAPDHおよびΔΔCT=ΔCTオリゴヌクレオチド−ΔCTリポフェクタミンである。各バーは、2〜3の個別の実験を示す。
4〜8週齢のC57BL/6マウスからの脾細胞を、RPMI完全培地で培養した。マウス脾細胞を5×106細胞/mlで24ウェルディッシュにプレートし、TEバッファー(10mMのトリス−HCl、pH7.5、1mMのEDTA)に溶解した本発明のTLR9特異的オリゴヌクレオチドベースの化合物で処理し、37℃で24時間インキュベートした。アンチセンス処理の後、細胞を次に、10μg/mlのTLR9アゴニストで24時間刺激した。処理および刺激の後、上清を収集し、細胞培養上清物中のIL−12およびIL−6分泌を、サンドイッチELISAで測定した
オリゴヌクレオチドベースの組成物のin vivo活性
本発明のアンチセンスオリゴヌクレオチドのin vivo活性を評価するために、5〜6週齢の雌C57BL/6マウス(N=3/群)に、本発明の例示のオリゴヌクレオチドベースの組成物を0.25、2、または5mg/kgで、またはPBSを、左側腹部に皮下注射した。オリゴヌクレオチドベースの組成物の投与の24時間後、マウスに、0.25mg/kgのTLRアゴニストを右側腹部に皮下注射した。TLRアゴニスト投与の2時間後、血液を採取し、血清IL−12濃度をELISAにより決定した。データは、IL−12の絶対濃度またはIL−12産生のパーセンテージとして示す。
本発明のアンチセンスオリゴヌクレオチドのin vivo活性の持続時間を評価するために、5〜6週齢の雌C57BL/6マウス(N=3/群)に、本発明の例示のオリゴヌクレオチドベースの組成物を5mg/kgで、またはPBSを、左側腹部に皮下注射した。オリゴヌクレオチドベースの組成物の投与の24時間後、0.25mg/kgのTLRアゴニストをマウスの右側腹部に、1、3、5、7、10または14日目に皮下注射した。TLRアゴニストの各投与の2時間後、血液を採取し、血清IL−12濃度をELISAにより決定した。データは、IL−12の絶対濃度またはIL−12産生のパーセンテージとして示す。
アンチセンス関連タンパク質および酵素による、オリゴヌクレオチドベースの化合物の選択的結合および切断
アンチセンス関連タンパク質および酵素の、本発明のオリゴヌクレオチドベースの化合物または対照オリゴヌクレオチドに結合および切断する特異性を評価するために、以下のように処理した:30mlのバッファー(10Xバッファー、Invitrogen)中の5’末端[γ―32P]ラベル標的mRNA(例えば配列番号21:10nMのヒト/マウスTLR7)および相補的RNAまたはDNA(10nM;ヒト/マウスTLR7)を85℃で5分間加熱し、室温に20分間冷却して、2本鎖のアニーリングを許容した。ヒトダイサー酵素(0.025U、Invitrogen)を反応溶液に加え、次に37℃で1時間インキュベートした。1mlの停止溶液(Invitrogen)および10mlのゲル負荷染料を試料溶液に加えて、よく撹拌した。試料を直ちに−80℃に冷凍した。RNA消化産物を16%変性PAGE上で分析し、ゲルをX線フィルムに暴露し、オートラジオグラムを現像した。結果を図13に示す。
当業者は、ルーチンの実験以上のものを用いることなく、本明細書に記載の特定の物質および手順の多数の等価物を認識し、または解明することができる。例えば、オリゴヌクレオチドとオーバーラップするアンチセンスオリゴヌクレオチドを用いてもよい。かかる等価物は本発明の範囲内と考えられ、以下のクレームに包含される。
Claims (17)
- 一本鎖RNA配列に相補的な2つのオリゴヌクレオチドを含む合成オリゴヌクレオチドベースの化合物であって、該オリゴヌクレオチドはその5’末端で結合されており、したがって前記オリゴヌクレオチドベースの化合物は2つのアクセス可能な3’末端を有し、かつ、前記オリゴヌクレオチドベースの化合物は、前記一本鎖RNA配列に特異的にハイブリダイズし、該一本鎖RNA配列の発現を阻害する、前記化合物。
- オリゴヌクレオチドが、それぞれが独立して15〜40ヌクレオチド長である、請求項1に記載のオリゴヌクレオチドベースの化合物。
- オリゴヌクレオチドが、ヌクレオチド結合を介して、または、非ヌクレオチドリンカーを介して、互いに結合されている、請求項1に記載のオリゴヌクレオチドベースの化合物。
- オリゴヌクレオチドが、1または2以上のリボヌクレオチド、デオキシリボヌクレオチド、ロックされた核酸、アラビノ糖ヌクレオチド、またはこれらの組み合わせを含有する、請求項1に記載のオリゴヌクレオチドベースの化合物。
- 少なくとも1つのオリゴヌクレオチドが修飾されている、請求項1に記載のオリゴヌクレオチドベースの化合物。
- 修飾オリゴヌクレオチドが、アルキルホスホナート、ホスホロチオアート、ホスホロジチオアート、メチルホスホナート、および非ヌクレオチドリンカーからなる群から選択される少なくとも1つのヌクレオチド間結合を有する、請求項5に記載のオリゴヌクレオチドベースの化合物。
- 修飾オリゴヌクレオチドが、2’−O−メチル、2’−O−メトキシ、2’−O−エトキシ、2’−O−メトキシエチル、2’−O−アルキル、2’−O−アリールおよび2’−O−アリルからなる群から選択される少なくとも1つの2’−O−置換ヌクレオチドを含有する、請求項5に記載のオリゴヌクレオチドベースの化合物。
- 請求項1〜7のいずれか一項に記載のオリゴヌクレオチドベースの化合物および生理学的に許容し得る担体を含む、組成物。
- 遺伝子発現を阻害することに用いる、請求項1〜7のいずれか一項に記載のオリゴヌクレオチドベースの化合物。
- オリゴヌクレオチドが、Bcl−2、EGFR、mdm2、MyD88、PCSK9、サバイビン、VEGFまたはTLRをコードするRNAに相補的である、請求項9に記載のオリゴヌクレオチドベースの化合物。
- TLRが、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、およびTLR9から選択される、請求項10に記載のオリゴヌクレオチドベースの化合物。
- 各オリゴヌクレオチドが、一本鎖RNA配列の異なる領域に相補的である、請求項9に記載のオリゴヌクレオチドベースの化合物。
- タンパク質が介在する疾患または障害を有する哺乳動物を治療的に処置する方法に使用するためのオリゴヌクレオチドベースの化合物であって、オリゴヌクレオチドが、前記タンパク質をコードする一本鎖RNAに相補的である、請求項1〜7のいずれか一項に記載のオリゴヌクレオチドベースの化合物。
- タンパク質が介在する疾患または障害を発症するリスクを有する哺乳動物における、該疾患または障害を予防する方法に使用するためのオリゴヌクレオチドベースの化合物であって、オリゴヌクレオチドが、前記タンパク質をコードする一本鎖RNAに相補的である、請求項1〜7のいずれか一項に記載のオリゴヌクレオチドベースの化合物。
- 疾患または障害が、癌、自己免疫障害、気道炎症、炎症性疾患、感染症、皮膚障害、アレルギー、喘息、細菌もしくはウイルスもしくは真菌感染症、または病原体による疾患から選択される、請求項13または14に記載のオリゴヌクレオチドベースの化合物。
- 1種または2種以上のワクチン、抗原、抗体、細胞毒性剤、アレルゲン、抗生物質、TLRアゴニスト、TLRアンタゴニスト、siRNA分子、miRNA分子、アンチセンスオリゴヌクレオチド、アプタマー、タンパク質、ペプチド、遺伝子治療ベクター、DNAワクチン、アジュバント、タンパク質活性のアンタゴニスト、キナーゼ阻害剤、化学療法剤、標的化治療剤、共刺激分子またはこれらの組み合わせと共に投与される、請求項9〜15のいずれか一項に記載のオリゴヌクレオチドベースの化合物。
- 1種または2種以上のワクチン、抗原、抗体、細胞毒性剤、化学療法剤、キナーゼ阻害剤、アレルゲン、抗生物質、アゴニスト、アンチセンスオリゴヌクレオチド、リボザイム、RNAi分子、siRNA分子、miRNA分子、アプタマー、タンパク質、遺伝子治療ベクター、DNAワクチン、アジュバント、共刺激分子またはこれらの組み合わせをさらに含む、請求項8に記載の組成物。
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PL2470656T3 (pl) | 2015-08-31 |
CN102712926A (zh) | 2012-10-03 |
HRP20150566T1 (hr) | 2015-07-17 |
EP3272870A1 (en) | 2018-01-24 |
CN104673795A (zh) | 2015-06-03 |
HK1210223A1 (en) | 2016-04-15 |
PT2470656E (pt) | 2015-07-16 |
EP2470656B1 (en) | 2015-05-06 |
CA2772352A1 (en) | 2011-03-17 |
ES2538347T3 (es) | 2015-06-19 |
CN102712926B (zh) | 2015-04-29 |
EP2470656A1 (en) | 2012-07-04 |
SMT201500140B (it) | 2015-09-07 |
EP2960333B1 (en) | 2017-10-04 |
SI2470656T1 (sl) | 2015-07-31 |
ES2646097T3 (es) | 2017-12-12 |
HUE026020T2 (en) | 2016-05-30 |
US20110082186A1 (en) | 2011-04-07 |
DK2470656T3 (da) | 2015-06-22 |
WO2011031520A1 (en) | 2011-03-17 |
US8431544B1 (en) | 2013-04-30 |
EP2960333A1 (en) | 2015-12-30 |
US20120016004A1 (en) | 2012-01-19 |
JP2013507905A (ja) | 2013-03-07 |
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