JP2022058394A - 一本鎖rnaを提供する方法 - Google Patents
一本鎖rnaを提供する方法 Download PDFInfo
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Abstract
Description
(式中、R1及びR2は、独立してヒドロキシ又はメトキシであり、W、X及びYは、独立して酸素、硫黄、セレン又はBH3である)を有するキャップ構造を含む。好ましい実施態様では、R1及びR2はヒドロキシであり、W、X及びYは酸素である。さらに好ましい実施態様では、R1及びR2の一方、好ましくはR1はヒドロキシであり、他方はメトキシであり、W、X及びYは酸素である。さらに好ましい実施態様では、R1及びR2はヒドロキシであり、W、X及びYの1つ、好ましくはXは、硫黄、セレン、又はBH3、好ましくは硫黄であり、他方は酸素である。さらに好ましい実施態様では、R1及びR2の一方、好ましくはR2はヒドロキシであり、他方はメトキシであり、W、X及びYの1つ、好ましくはXは、硫黄、セレン、又はBH3、好ましくは硫黄であり、他方は酸素である。
EtOH:エタノール
h:時間(複数可)
hPa:ヘクトパスカル
min:分(複数可)
mM:ミリモル濃度(10-3mol/l)
MPa:メガパスカル
nt:ヌクレオチド(複数可)
sec:秒(複数可)
v/v:体積%
IVT RNAのセルロース精製
他に指示がない限り、中程度サイズの繊維(Sigma-Aldrich、カタログ番号C6288)及び1×STE緩衝液(10mM TRIS、pH7.0、50mMのNaCl、20mMのEDTA)からなるセルロース粉末を精製手法に使用した。すべての実験は、室温で行われた。
「負の」の精製手法は、16%EtOHを含有する1×STE緩衝液中のIVT RNAを伴うセルロースのインキュベーションに基づく。この条件は、ssRNAが可溶性画分に残っている間に、セルロースへのdsRNAの選択的結合を可能にする。
「陽性」精製手法の原理は、40%EtOHを含有する1×STE緩衝液中でセルロースとともにIVT RNAをインキュベートすることにより、最初にすべてのRNAをセルロースに結合させることである。第2の工程では、ssRNAは、これらの条件下でdsRNAがセルロース繊維に結合したままである間に、16%EtOHを含有する1×STE緩衝液中でのインキュベーションにより選択的に放出される。
セルロース精製から得られたRNAは、0.1容量の3M酢酸ナトリウム(pH4.0)及び1容量のイソプロパノールを添加することによって沈殿させた。ボルテックス後、サンプルを1時間、-20℃でインキュベートし、続いて、10分間、14,000×gで間遠心分離した。RNAペレットを200μlの氷冷した70%(v/v)EtOHで洗浄し、風乾し、適切な体積のヌクレアーゼ不含H2Oに溶解した。RNA濃度は、Nanodropシステム(Eppendorf)を用いて分光光度的に測定された。
dsRNA及びRNA-DNAハイブリッド混入物の量を決定するために、異なる濃度のRNAサンプルの連続希釈物を調製し、増加した量のRNA(通常40ng、200ng及び1,000ng)をナイロンブロッティング膜(Nytran SuPerCharge(SPC)ナイロンブロッティング膜(GE Healthcare Life Sciences、カタログ番号10416216))上にスポット(0.5μl)した。次に、膜は、5%(w/v)スキムミルク粉末を含有するTBS-T緩衝液(20mMのTRIS、pH7.4、137mMのNaCl、0.1%(v/v)TWEEN-20)中で1時間遮断された。dsRNAの検出のために、膜は、1%(w/v)スキムミルク粉末を含有するTBS-T緩衝液中、1:10,000の比率で希釈したJ2 dsRNA特異的マウスmAb(English&Scientific Consulting、Szirak、Hungary)とともに1時間、インキュベートされた。指示されている場合、1:10,000の比で希釈したS9.6 RNA-DNAハイブリッド特異的マウスmAb IgG2a(KeraFAST、カタログ番号ENH001)を用いて、RNA-DNAハイブリッド混入物を検出した。TBS-Tで洗浄した後、膜は、1%(w/v)スキムミルク粉末を含有するTBS-T緩衝液中、1:10,000の比で希釈された、HRPをコンジュゲートしたロバ抗マウスIgG(Jackson ImmunoResearch、カタログ番号715-035-150)とともに1時間、インキュベートし、TBS-Tで洗浄し、Amersham ECLプライムウェスタンブロッティング検出試薬(Fisher Scientific、カタログ番号RPN2232)及びChemiDoc MP画像化システム(BIO-RAD)を用いて発色させた。指示されている場合、ハイブリダイゼーションシグナル強度は、Image Lab 5.1ソフトウェア(BIO-RAD)を用いたデンシトメトリーによって定量化された。
精製RNAの完全性をモニターし、ドットブロットにロードされた量を検証するために、アガロースゲル電気泳動を使用した。ドットブロッティングのために調製した40ng/μlの連続RNA希釈液の等量のRNA(例えば、2μl)を分析した。RNAサンプルは、Masek等(Anal. Biochem. 336 (2005)、46-50)に従って、2μlのRNA(80ng)を6μlのホルムアミドと混合し、5分間、65℃でインキュベートすることによって変性し、その後、0.005%(v/v)のGelRed(商標)核酸ゲル染色剤(Biotium Inc.、カタログ番号41003)を含有する1.4%(w/v)アガロース上にロードした。電気泳動は、泳動緩衝液としてTAE(40mMのTRIS酢酸塩、1mMのEDTA)を用いて、100Vで20分間行われ、続いてGel Doc(商標)EZ Imagerシステム(BIO-RAD)を用いてゲルを画像化した。
最初にIVT RNAからdsRNA混入物を除去するためにセルロースを適用する実施可能性を試験するために、簡単なプルダウン実験を行った。IVT反応からの塩化リチウム(LiCl)沈殿によって予備精製された、50μgの2,500nt長のN1-メチル-プソイドウリジン(m1Ψ)修飾されたIVT RNAを、16%(v/v)EtOHを含有する1×STE緩衝液の存在下で、0.1gのセルロースとともにインキュベートした。遠心分離後、上清中の未結合RNAを沈殿させた。EtOHを含有しない1×STE中のセルロースの再懸濁、遠心分離及び上清の沈殿により、セルロース結合RNAを回収した。両方の画分からのRNA並びに出発RNA材料のRNAのdsRNA含量を、dsRNA特異的J2抗体を用いたドットブロットによって分析した。RNAの完全性は、アガロースゲル電気泳動によってモニターされた。
次のステップで、上記の精製方法(実施例1参照)を、ミクロ遠心分離スピンカラムを用いるために、セルロースから未結合RNAを分離するように適合させた。この技術の利点は、遠心分離によってセルロースから液体、及びしたがって未結合RNAを完全に除去することである。さらに、最大18%(v/v)又は20%(v/v)の、IVT RNAのセルロースとのインキュベーション中のEtOH濃度を増加させることがdsRNA除去の効率を増加させるかどうかを試験した。最初に、磁気ビーズによるIVT反応から予備精製された、50μgの1,500nt長のシプソイドウリジン(Ψ)修飾及びD2キャップされたIVT RNAを、0.1gのセルロースを有するマイクロ遠心分離スピンカラムにおいて、16%(v/v)、18%(v/v)又は20%(v/v)のEtOHを含有する1×STE緩衝液の存在下でインキュベートした。遠心分離後、カラムの遠心分離によって未結合RNAを回収し、沈殿させた。セルロース結合RNAは、EtOHを含有しない1×STEをカラムに添加し、激しく振盪してセルロースを再懸濁し、最後に遠心分離及び沈殿させることにより回収された。両方の画分並びに出発RNA材料からのRNAのdsRNA含量を、dsRNA特異的J2抗体を用いたドットブロットによって分析した。第2の膜には、同量の異なるRNA画分をロードし、RNA/DNAハイブリッド特異的S9.6抗体とハイブリダイズさせて、これらのIVT RNA混入物がまたセルロース精製によって除去され得るかどうかを試験した。
マイクロ遠心分離スピンカラムを用いた上記の方法(実施例2参照)によるセルロース精製の複数回のサイクルが、dsRNA除去の効率を高めるかどうかを試験するために、IVT反応からの塩化リチウム(LiCl)沈殿によって予備精製された、100μgの2,500nt長のm1Ψ修飾されたIVT RNAは、16%(v/v)EtOHを含有する1×STE緩衝液を用いて上記のように1×、2×又は3×で精製された。さらに、セルロースによって精製されたRNAは、大腸菌RNaseIII(0.2U/100μgのRNA)で30分間、37℃で処理されたか、またWeissman等(上記)によって記載されたプロトコールに従ってHPLCで精製されたIVT RNAと比較された。すべてのRNAのdsRNA含量は、dsRNA特異的J2抗体を用いたドットブロットにより分析され、ハイブリダイゼーションシグナルの密度分析によって定量化された。RNA完全性は、アガロースゲル電気泳動によってモニターされた。
dsRNA混入物の除去が、上記の実験(Sigma-Aldrich、カタログ番号C6288)において使用した特定のセルロースブランドに限定されるのかどうか、又は他の供給業者からのセルロースもまた使用することができるかどうかを試験するために、本発明者等は、Macherey-Nagelからの2つの他のセルロースタイプ(MN 100、MN 2100)の性能を試験した。最初に、IVT反応から塩化リチウム(LiCl)沈殿によって予備精製された、100μgの1,500nt長のm1Ψ修飾されたIVT RNAは、マイクロ遠心分離スピンカラム中で、16%(v/v)EtOHを含有する1×STE緩衝液の存在下で、0.15gの異なるタイプのセルロースとともにインキュベートされた。遠心分離後、未結合RNAは、カラムを遠心分離し、フロースルー中のRNAを沈殿させることによって回収された。セルロース結合RNAは、カラムに1×STEを添加し、続いて、激しく振盪してセルロースを再懸濁し、最後に遠心分離及び沈殿によって回収された。すべてのRNAサンプルのdsRNA含量は、dsRNA特異的J2抗体を用いたドットブロットにより分析され、ハイブリダイゼーションシグナルの密度分析によって定量化された。RNA完全性は、アガロースゲル電気泳動によってモニターされた。
重要な点は、セルロース精製法が拡張性であるかどうかを試験することであった。したがって、実験は、磁気ビーズによるIVT反応により予備精製された、5mgの1,900nt長のD1キャップされたIVT RNAからdsRNA混入物を除去するために実施された。RNAは、16%(v/v)EtOHを含有する15mlの1×STE緩衝液中の1.5gのセルロース(Sigma、カタログ番号C6288)とともにインキュベートされた。未結合RNAは、真空駆動フィルターデバイス(孔径0.45μM)によってセルロースから分離され、沈殿された。別の5mgの同じRNAを用いて、2精製サイクルを実施した。両方の精製RNAのdsRNA含量は、dsRNA特異的J2抗体を用いたドットブロットにより分析され、ハイブリダイゼーションシグナルの強度の密度分析により定量化された。RNA完全性は、アガロースゲル電気泳動によってモニターされた。
次のステップで、EtOH濃度を16%(v/v)に減少させることによってssRNA画分を選択的に放出する前に、高EtOH濃度の存在下でIVT RNA調製物の全RNA成分をセルロースに最初に結合させることが実施可能かどうかを試験した。この条件下で、dsRNA混入物はセルロース材料に結合したままであり、したがってssRNAから分離されるべきである(「陽性」精製)。この手法は、EtOHの存在下でセルロースに結合しない非核酸混入物(例えば、タンパク質、遊離ヌクレオチド)の除去も可能にするため、「陰性」精製と比較して有利である。したがって、様々な長さ(1,300nt、2,500nt及び>10,000nt)及びキャップ構造(D1、D2、キャップなし)を有する、400μgの3つのIVT RNAは、40%(v/v)EtOHを含有する1×STE緩衝液を用いて、マイクロ遠心分離スピンカラム中の0.12gのセルロースに完全に結合させる実験を行った。ssRNAは、16%(v/v)EtOHを含有する1×STE緩衝液で溶出され、1.2mgの新鮮なセルロースを含有する第2のスピンカラムに移された。激しく振盪しながらインキュベーション及び遠心分離後、フロースルー中のRNAを沈殿させ、dsRNA特異的J2抗体を用いたドットブロッティングによりdsRNA混入物を分析した。RNA完全性は、アガロースゲル電気泳動によってモニターされた。
二本鎖核酸の安定性は、環境のイオン強度によって影響される。高塩濃度は二本鎖構造の形成を促進するが、一本鎖核酸へのそれらの解離は低塩濃度下で増強される。セルロースによるdsRNA除去効率における緩衝液のイオン強度の影響を分析するために、IVT反応から塩化リチウム(LiCl)沈殿によって予備精製された、1,300nt長のm1Ψ修飾されたIVT RNAは、1.5mlチューブにおいて、40%(v/v)EtOH及び様々な濃度のNaCl(0-150mM)を含有する500μlの1×STE緩衝液中の0.1gのセルロースとともにインキュベートされた。遠心分離後、上清を除去し、セルロースを16%(v/v)EtOHを含有する、500μlの対応する1×STE緩衝液に再懸濁して、ssRNAを放出させた。遠心分離後、上清を集め、RNAを沈殿により回収した。最終工程で、セルロースは、EtOHを含有しない、500μlの対応する1×STE緩衝液に再懸濁し、遠心分離し、上清の沈殿によってRNAを回収した。両方の画分(16%EtOH溶出液、0%EtOH溶出液)からのRNA、並びに出発RNA材料(IVT RNA)からのRNAのdsRNA含量は、dsRNA特異的J2抗体を用いたドットブロットにより分析され、ハイブリダイゼーションシグナルの密度分析によって定量化された。RNAの完全性は、アガロースゲル電気泳動によってモニターされた。
「陽性」精製手法を用いたセルロースによるdsRNA混入物からのssRNAの分離は実現可能であるため(実施例6及び7参照)、FPLCの精製プロトコールを適合させる試みがなされた。4gのセルロースは、XK16/20カラムを充填するために、固定相として使用された。40%(v/v)EtOHを含有する1×STE緩衝液で平衡化した後、IVT反応から塩化リチウム(LiCl)沈殿によって予備精製された、500μgの1,300nt長のm1Ψ修飾されたIVT RNAをカラムにロードした。結合ssRNA及びdsRNAは、緩衝液のEtOH濃度をそれぞれ16%(v/v)及び0%(v/v)に低減させることによって溶出され、画分を回収した。RNAを沈殿によって回収し、両画分(F1:16%EtOH溶出液、F2:0%EtOH溶出液)からのRNA、並びに出発RNA材料(インプットRNA)からのRNAのdsRNA含量をdsRNA特異的J2抗体を用いたドットブロットによって分析された。RNAの完全性は、アガロースゲル電気泳動によってモニターされた。
「陽性」セルロース精製手法のプロトコールを最適化するために、dsRNA除去及びRNA回収の効率における様々なEtOH濃度の影響を試験した。磁気ビーズによるIVT反応から予備精製された、200μgの1,500nt長のD1キャップされたIVT RNAは、マイクロ遠心分離スピンカラムにおいて、40%(v/v)EtOHを含有する500μlの1×STE緩衝液中の0.1gの洗浄セルロースとともにインキュベートされた。セルロース結合ssRNAは、6、10、12、14、16、18、20又は24%(v/v)のEtOHを含有する1×STE緩衝液で溶出され、沈殿により溶出液から回収された。様々な溶出液から得られたRNA並びに出発RNA材料(インプットRNA)のRNAのdsRNA含量は、dsRNA特異的J2抗体を用いたドットブロットにより分析され、ハイブリダイゼーションシグナルの密度分析によって定量化された。RNAの完全性は、アガロースゲル電気泳動によって確認された。
「陽性」セルロース精製手法をスケールアップするためには、過剰にロードすることによって引き起こされるRNA喪失を最小にする、セルロースのRNA結合能を知ることが重要である。RNA結合能を決定するために、本発明者等は、マイクロ遠心分離スピンカラムにおいて40%(v/v)EtOHを含有する500μlの1×STE緩衝液中で、磁気ビーズによってIVT反応から予備精製された、25μg、50μg、100μg、250μg、500μg、750μg、1,000μg又は1,500μgの1,500nt長のD1キャップされたIVT RNAとともに固定量の洗浄セルロース(100mg、Sigma、C6288)をインキュベートした。遠心分離後、ssRNAは、16%(v/v)のEtOHを含有する500μlの1×STE緩衝液で溶出された。最後に、なおもセルロースに結合したRNAをH2O(0%(v/v)EtOH)とのインキュベーションによって放出させた。フロースルー(40%(v/v)EtOH)中、及び16%(v/v)と0%(v/v)の両溶出液中のRNAを沈殿により回収し、回収されたRNAの量を分光光度法で決定した。さらに、16%(v/v)EtOH溶出液並びに出発RNA材料(インプットRNA)から得られたRNAのdsRNA含量は、dsRNA特異的J2抗体を用いたドットブロットにより分析され、個々のサンプル中におけるdsRNA除去効率をモニターした。これらのRNAの完全性は、アガロースゲル電気泳動によってモニターされた。
上記のように、IVT RNAは、T7 RNAポリメラーゼの異常な活性に起因するdsRNA混入物を含有する。しかしながら、dsRNAは、RIG-1、MDA5及びTLR3を含む異なる細胞センサーを活性化させることによって炎症性サイトカイン(インターフェロンなど)を誘導し、さらに、プロテインキナーゼR(PKR)及びオリゴアデニレートシンテターゼ(OAS)を活性化することによって翻訳を直接に阻害する。本発明の方法に供されたIVT RNAがより少ない炎症性サイトカインを誘導するかどうか、及び/又は本発明の方法に供されていないIVT RNAと比較してより効率的に翻訳され得るかどうかを試験するために、マウスエリスロポエチン(EPO)をコードするIVT RNAは、未精製のままとしたか、又はセルロース材料(0.12gセルロース(Sigma、C6288))でそれぞれ充填された2つのスピンカラムを使用する2工程手法によって精製した。最初に、IVT RNAは、第1のスピンカラムを用いて(すなわち、dsRNA及びssRANをセルロース材料に結合させるために、IVT RNAを第1のスピンカラムにおいて、40%(v/v)を含有する1×STE緩衝液の存在下でセルロース材料とともにインキュベートし;第1のスピンカラムに遠心力を適用し;フロースルーを廃棄し;16%(v/v)EtOHを含有する1×STE緩衝液を添加し、第1スピンカラムに遠心力を適用することによって、第1のスピンカラムからssRNAを溶出して)、上記される陽性精製手法に供された。次に、このようにして得られたssRNAを含有する溶出液は、第2のスピンカラムを用いて(すなわち、第2のスピンカラムにおいてssRNAを含有する溶出液をセルロース材料とともにインキュベートし;第2のスピンカラムに遠心力を適用し;フロースルーを回収して)、上記される陰性精製手法に供された。次に、第2のスピンカラムから得られたフロースルーは、イソプロパノール/酢酸ナトリウムを用いて沈殿させ、H2Oに再溶解させた。TransIT(Mirus Bio)を用いて処方後、IVT RNAは、3μgのRNA/動物の用量でマウス(n=4)に腹腔内注射された。血液を注射後の2、6、及び24時間に採取し、血漿サンプルを回収した。コントロールマウスは、TransITのみを注射された。マウスインターフェロンアルファ(IFN-α)及びマウスEPOのレベルは、特異的ELISAアッセイ(マウスインターフェロンアルファ特異的ELISA(eBioscience)、マウスEPO特異的DuoSet ELISA発色キット(R&D))を用いて、測定された。
Claims (48)
- 一本鎖RNA(ssRNA)を提供する方法であって、
(i)インビトロ転写によって生成されたssRNAを含むRNA調製物を提供すること;
(ii)セルロース材料への二本鎖RNA(dsRNA)の結合を可能にする条件下で、RNA調製物をセルロース材料と接触させること;及び
(iii)セルロース材料へのdsRNAの結合を可能にする条件下で、セルロース材料からssRNAを分離すること
を含む、方法。 - インビトロ転写によってssRNAを含むRNA調製物を生成する工程をさらに含む、請求項1に記載の方法。
- 工程(ii)及び(iii)が、セルロース材料へのdsRNAの結合を可能にし、セルロース材料へのssRNAの結合を可能にしない条件下で行われる、請求項1又は2に記載の方法。
- 工程(ii)が、ssRNAを含むRNA調製物を、振盪及び/又は撹拌下で、好ましくは少なくとも5分間、より好ましくは少なくとも10分間、セルロース材料と混合することを含む、請求項3に記載の方法。
- 工程(ii)において、RNA調製物が、ssRNA及び第1の緩衝液を含む液体として提供され、及び/又はセルロース材料が第1の緩衝液中の懸濁液として提供され、第1の緩衝液が、セルロース材料へのdsRNAの結合を可能にし、セルロース材料へのssRNAの結合を可能にしない濃度で、水、エタノール及び塩、好ましくは塩化ナトリウムを含む、請求項4に記載の方法。
- 第1の緩衝液中のエタノール濃度が14-20%(v/v)、好ましくは14-16%(v/v)である、請求項5に記載の方法。
- 第1の緩衝液中の塩の濃度が15-70mM、好ましくは20-60mMである、請求項5又は6に記載の方法。
- 第1の緩衝液が、緩衝物質、好ましくはトリス(ヒドロキシメチル)アミノメタン(TRIS)、及び/又はキレート剤、好ましくはEDTAをさらに含む、請求項5から7の何れか一項に記載の方法。
- 工程(iii)において、RNA調製物、セルロース材料、及び第1の緩衝液の混合物がチューブに入れられ、工程(iii)が、(1)液相及び固相が分離されるようにチューブに重力又は遠心力を適用すること;並びに(2)ssRNAを含む上清を回収するか又はセルロース材料を除去することを含む、請求項5から8の何れか一項に記載の方法。
- 工程(iii)において、RNA調製物、セルロース材料、及び第1の緩衝液の混合物がスピンカラム又はフィルターデバイスに入れられ、工程(iii)が、(1’)液相及び固相が分離されるようにスピンカラム又はフィルターデバイスに重力、遠心力、圧力、又は真空を適用すること;並びに(2’)ssRNAを含むフロースルーを回収することを含む、請求項5から8の何れか一項に記載の方法。
- 工程(ii)及び(iii)が1回又は2回以上、反復され、工程(ii)及び(iii)の1サイクルのうち工程(iii)の後に得られたssRNA調製物が、次サイクルの工程(ii)におけるRNA調製物として使用され、工程(ii)及び(iii)の各サイクルのうち工程(ii)において、新鮮なセルロース材料が使用される、請求項3から10の何れか一項に記載の方法。
- 工程(ii)がdsRNA及びssRNAのセルロース材料への結合を可能にする条件下で行われ、工程(iii)がdsRNAのセルロース材料への結合を可能にし、ssRNAのセルロース材料への結合を可能にしない条件下で行われる、請求項1又は2に記載の方法。
- 工程(II)が、(1)ssRNAを含むRNA調製物を、振盪及び/又は撹拌下で、好ましくは少なくとも5分間、より好ましくは少なくとも10分間、セルロース材料と混合すること;並びに(2)dsRNA及びssRNAが結合しているセルロース材料を残部から分離することを含む、請求項12に記載の方法。
- 工程(ii)において、RNA調製物が、ssRNA及び第2の緩衝液を含む液体として提供され、及び/又はセルロース材料が第2の緩衝液中の懸濁液として提供され、第2の緩衝液が、セルロース材料へのdsRNA及びssRNAの結合を可能にする濃度で、水、エタノール及び塩、好ましくは塩化ナトリウムを含む、請求項13に記載の方法。
- 第2の緩衝液中のエタノールの濃度が、少なくとも35%(v/v)、好ましくは38-42%(v/v)である、請求項14に記載の方法。
- 第2の緩衝液中の塩の濃度が、15-70nM、好ましくは20-60mMである、請求項14又は15に記載の方法。
- 第2の緩衝液が、緩衝物質、好ましくはトリス(ヒドロキシメチル)アミノメタン(TRIS)、及び/又はキレート剤、好ましくはEDTAをさらに含む、請求項14から16の何れか一項に記載の方法。
- 工程(ii)(2)において、工程(ii)(1)で得られたRNA調製物とセルロース材料の混合物がチューブに入れられ、工程(ii)(2)が、(2a)液相及び固相が分離されるようにチューブに重力又は遠心力を適用すること;並びに(2b)上清を除去するか、又はdsRNA及びssRNAが結合しているセルロース材料を回収することを含む、請求項14から17の何れか一項に記載の方法。
- 工程(ii)(2)において、工程(ii)(1)で得られたRNA調製物とセルロース材料の混合物がスピンカラム又はフィルターデバイスに入れられ、工程(ii)(2)が、(2a’)液相及び固相が分離されるようにスピンカラム又はフィルターデバイスに重力、遠心力、圧力、又は真空を適用すること;並びに(2b’)フロースルーを廃棄することを含む、請求項14から17の何れか一項に記載の方法。
- 工程(ii)が、(3)dsRNA及びssRNAが結合しているセルロース材料に第2の緩衝液のアリコートを添加すること;(4)得られた混合物を、振盪及び/又は撹拌下で、好ましくは少なくとも5分間、より好ましくは少なくとも10分間、インキュベートすること;並びに(5)dsRNA及びssRNAが結合しているセルロース材料を液相から分離すること;並びに、任意選択的に(6)工程(3)-(5)を1回又は2回以上、反復することをさらに含む、請求項14から19の何れか一項に記載の方法。
- 工程(iii)が、(1)dsRNA及びssRNAが結合しているセルロース材料を、振盪及び/又は撹拌下で、好ましくは少なくとも5分間、より好ましくは10分間、第1の緩衝液と混合することであって、第1の緩衝液が、dsRNAのセルロース材料への結合を可能にし、ssRNAのセルロース材料への結合を可能にしない濃度で、水、エタノール及び塩、好ましくは塩化ナトリウムを含む、混合すること;並びに(2)ssRNAを含む液相をセルロース材料から分離することを含む、請求項12から20の何れか一項に記載の方法。
- 第1の緩衝液中のエタノールの濃度が14-20%(v/v)、好ましくは14-16%(v/v)である、請求項21に記載の方法。
- 第1の緩衝液中の塩の濃度が15-70mM、好ましくは20-60mMである、請求項21又は22に記載の方法。
- 第1の緩衝液が、緩衝物質、好ましくはトリス(ヒドロキシメチル)アミノメタン(TRIS)、及び/又はキレート剤、好ましくはEDTAをさらに含む、請求項21から23の何れか一項に記載の方法。
- 工程(iii)において、セルロース材料と第1の緩衝液の混合物がチューブに入れられ、工程(iii)(2)が、(2a)液相及び固相が分離されるようにチューブに重力又は遠心力を適用すること;並びに(2b)ssRNAを含む上清を回収するか又はセルロース材料を除去することを含む、請求項21から24の何れか一項に記載の方法。
- 工程(iii)において、セルロース材料と第1の緩衝液の混合物がスピンカラム又はフィルターデバイスに入れられ、工程(iii)(2)が、(2a’)スピンカラム又はフィルターデバイスに重力、遠心力、圧力、又は真空を適用すること;及び(2b’)ssRNAを含むフロースルーを回収することを含む、請求項21から24の何れか一項に記載の方法。
- 工程(ii)及び(iii)が1回又は2回以上、反復され、工程(ii)及び(iii)の1サイクルのうち工程(iii)の後に得られたssRNA調製物が、次サイクルの工程(ii)におけるRNA調製物として使用され、工程(ii)及び(iii)の各サイクルのうち工程(ii)において、新鮮なセルロース材料が使用される、請求項12から26の何れか一項に記載の方法。
- 工程(ii)において、セルロース材料がカラムに入れられ、工程(ii)が、dsRNA及びssRNAのセルロース材料への結合を可能にする条件下で、カラムにRNA調製物をロードすることを含み、工程(iii)が、dsRNAのセルロース材料への結合を可能にし、ssRNAのセルロース材料への結合を可能にしない条件下で、セルロース材料からssRNAを溶出することを含む、請求項12に記載の方法。
- 工程(ii)において、RNA調製物が提供され、ssRNAを含む液体及び第2の緩衝液としてカラムにロードされ、第2の緩衝液が、dsRNA及びssRNAのセルロース材料への結合を可能にする濃度で、水、エタノール及び塩、好ましくは塩化ナトリウムを含む、請求項28に記載の方法。
- 第2の緩衝液中のエタノール濃度が少なくとも35%(v/v)、好ましくは38-42%(v/v)である、請求項29に記載の方法。
- 第2の緩衝液中の塩の濃度が15-70mM、好ましくは20-60mMである、請求項29又は30に記載の方法。
- 第2の緩衝液が、緩衝物質、好ましくはトリス(ヒドロキシメチル)アミノメタン(TRIS)、及び/又はキレート剤、好ましくはEDTAをさらに含む、請求項29から31の何れか一項に記載の方法。
- 工程(iii)が、溶離液として第1の緩衝液を使用して実施され、第1の緩衝液が、dsRNAのセルロース材料への結合を可能にし、ssRNAのセルロース材料への結合を可能にしない濃度で、水、エタノール及び塩、好ましくは塩化ナトリウムを含む、請求項28から32の何れか一項に記載の方法。
- 第1の緩衝液中のエタノール濃度が14-20%(v/v)、好ましくは14-16%(v/v)である、請求項33に記載の方法。
- 第1の緩衝液中の塩の濃度が15-70mM、好ましくは20-60mMである、請求項33又は34に記載の方法。
- 第1の緩衝液が、緩衝物質、好ましくはトリス(ヒドロキシメチル)アミノメタン(TRIS)、及び/又はキレート剤、好ましくはEDTAをさらに含む、請求項33から35の何れか一項に記載の方法。
- RNA調製物が、T3、T7及びSP6 RNAポリメラーゼからなる群から選択されるRNAポリメラーゼを使用することによって生成される、請求項1から36の何れか一項に記載の方法。
- 工程(ii)の前に、RNA調製物が、少なくとも1つの予備精製処理に供される、請求項1から37の何れか一項に記載の方法。
- 少なくとも1つの予備精製処理が、以下:好ましくは塩化リチウムを用いた核酸の沈殿;核酸の磁気ビーズへの結合;限外濾過;及び好ましくは二重鎖特異的ヌクレアーゼ(DSN)を用いたDNAの分解のうちの一又は複数を含む、請求項38に記載の方法。
- ssRNAが、アンチセンスRNA、siRNA、又はmiRNAなどのmRNA又は阻害RNAである、請求項1から39の何れか一項に記載の方法。
- ssRNAが、少なくとも2700nt、好ましくは少なくとも3000nt、より好ましくは少なくとも3500nt、より好ましくは少なくとも4500のntの長さを有する、請求項1から40の何れか一項に記載の方法。
- セルロース材料が、セルロース繊維、好ましくは分配クロマトグラフィー試薬としての使用に適したグレードのセルロース繊維を含む、請求項1から41の何れか一項に記載の方法。
- 工程(ii)においてRNA調製物と接触させる前に、セルロース材料が洗浄セルロース材料として提供される、請求項1から42の何れか一項に記載の方法。
- セルロース材料の洗浄が、(I)セルロース材料を、振盪及び/又は撹拌下で、好ましくは少なくとも5分間、より好ましくは少なくとも10分間、洗浄溶液と混合すること;並びに(II)液体を除去するか又はセルロース材料を回収すること;並びに任意選択的に(III)工程(I)及び(II)を1回又は2回以上、反復することを含む、請求項43に記載の方法。
- 洗浄溶液が、(A)工程(ii)がdsRNAの洗浄セルロース材料への結合を可能にし、ssRNAの洗浄セルロース材料への結合を可能にしない条件下で行われる場合、請求項5から8の何れか一項に定義された第1の緩衝液、又は(B)工程(ii)がdsRNA及びssRNAの洗浄セルロース材料への結合を可能にする条件下で行われる場合、請求項14から17の何れか一項に定義された第2の緩衝液の組成を有する、請求項44に記載の方法。
- 請求項1から45の何れか一項に記載の方法によって得ることができるssRNA。
- dsRNAを実質的に含まず、好ましくはdsRNA及びDNAを実質的に含まない、請求項46に記載のssRNA。
- 治療に用いるための、請求項46又は47に記載のssRNA。
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