JP2018512110A - GST−π遺伝子を調節するためのRNA干渉剤 - Google Patents
GST−π遺伝子を調節するためのRNA干渉剤 Download PDFInfo
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Abstract
Description
センス鎖及びアンチセンス鎖を含むGST-πの発現を阻害するための核酸分子であって、前記鎖が二重鎖領域を形成する核酸分子。当該核酸分子は、GST-πの発現を阻害するためのsiRNA分子であってよく、修飾又は化学的修飾された1つ以上のヌクレオチドを含むことができる。
例示的な標的ヒトグルタチオンS-トランスフェラーゼ(ヒトGST-π)mRNAの核酸配列は、GenBankアクセッション番号NM_000852.3(hGSTP1)に開示されており、986ヌクレオチドの長さである。
本発明の実施形態は、修飾又は化学的修飾されたsiRNA分子を包含し、遺伝子サイレンシングの活性及び効力の増加などの治療用途のための強化された特性を提供することができる。本発明は、遺伝子調節及び遺伝子サイレンシングのためのsiRNA分子の活性及び効力を失うことなく、血清安定性に優れ、さらにオフターゲット効果が低減した修飾又は化学的修飾されたsiRNA分子を提供する。いくつかの態様では、本発明は、siRNAの安定性及び有効性を増強する様々な組み合わせの修飾又は化学修飾を有するsiRNAを提供する。
本発明の実施形態は、GST-π及び/又はGST-πタンパク質の発現をダウンレギュレート又は阻害するために使用することができるRNAi分子を提供することができる。
RNA干渉(RNAi)は、短い干渉RNA(siRNA)によって媒介される動物における配列特異的転写後遺伝子サイレンシングを意味する。例えば、Zamoreら、Cell、2000、Vol. 101、25〜33頁; Fireら、Nature、1998、Vol. 391、806811頁; Sharp、Genes&Development、1999、Vol. 13、pp. 139-141参照。
いくつかの態様において、RNAi分子は、RISC活性RNAi分子を生成するようにプロセシングされるダイサー基質として適した長さにすることができる。例えば、Rossiら、US2005/0244858参照。
本発明の核酸分子及びRNAi分子は、分子の直接的な適用によって、又は担体若しくは希釈剤と組み合わせた分子を用いて、細胞又は組織に送達することができる。
トランスフェクションの1日前に、10%FBSを含む100μlのDMEM(HyCloneカタログ番号SH30243.01)を96ウェルプレートに2×103細胞/ウェルで播種し、5%CO2の空気中で加湿雰囲気を含む37℃インキュベーターで培養した。トランスフェクションの前に、培地を、2%FBSを含む90μlのOpti-MEM I還元血清培地(Life Technologiesカタログ番号31985-070)に変更した。その後、0.2μlのLipofectamine RNAiMax(Life Technologiesカタログ番号13778-100)を4.8μlのOpti-MEM Iと室温で5分間混合した。次に、1μlのsiRNAを4μlのOpti-MEM Iと混合し、LF2000溶液と混合し、ボルテックスなしで穏やかに混合した。室温で5分後、混合物を室温でさらに10分間インキュベートし、RNA-RNAiMax複合体を形成させた。さらに、10μlのRNA-RNAiMax複合体をウェルに添加し、プレートを手で静かに振盪した。細胞を5%CO2の空気中で加湿雰囲気を含む37℃のインキュベーター中で2時間インキュベートした。培地を、2%FBSを含む新鮮なOpti-MEM I還元血清培地に交換した。トランスフェクションの24時間後、細胞を氷冷PBSで1回洗浄した。細胞を室温で5〜30分間、50μlのCell-to-Ct溶解緩衝液(Life Technologiesカタログ番号4391851C)で溶解した。5μlの停止溶液を加え、室温で2分間インキュベートした。mRNAレベルはTAQMANを用いたRT-qPCRにより直ちに測定した。サンプルは-80℃で凍結し、後にアッセイすることができた。
0.2mg/mlのsiRNAを37℃で10%ヒト血清とともにインキュベートした。特定の時点(0、5、15及び30分)で、200μlの試料を等分し、抽出溶媒(クロロホルム:フェノール:イソアミルアルコール=24:25:1)200μlで抽出した。サンプルをボルテックスし、室温で10分間、13,000rpmで遠心分離し、次いで、上層溶液を移し、0.45μmのフィルターで濾過した。濾液を300μlのHPLC注入バイアルに移した。LCMSの場合、移動相はMPA:H2O中100mM HFIP+7mM TEA、MPB:50%メタノール+50%アセトニトリルとした。カラム:Waters Acquity OST 2.1×50mm、1.7μmを使用した。
PsiCHECK-2 (F)プラスミド挿入物:
配列番号285
ctcgag gggcaacTGAAGCCTTTTGAGACCCTGcTgTcccag gcggccgc
PsiCHECK-2 (R)プラスミド挿入物:
配列番号286
ctcgag cTgggacagCAGGGTCTCAAAAGGCTTCagTTgccc gcggccgc
PsiCHECK-2 (Fmi1)プラスミド挿入物:
配列番号287
ctcgag gggcaacTCTACGCAAAACAGACCCTGcTgTcccag gcggccgc
PsiCHECK-2 (Fmi2)プラスミド挿入物:
配列番号288
ctcgag gggcaacTCTACGCAAAACAGACCCTGcT CTACGCAAAACAGACCCTGcT gTcccag gcggccgc
PsiCHECK-2 (Fmi3)プラスミド挿入物:
配列番号289
ctcgag gggcaacTCTACGCAAAACAGACCCTGcT CTACGCAAAACAGACCCTGcT CTACGCAAAACAGACCCTGcT gTcccag gcggccgc
PsiCHECK-2 (Fmi4)プラスミド挿入物:
配列番号290
ctcgag gggcaacTCTACGCAAAACAGACCCTGcT CTACGCAAAACAGACCCTGcT CTACGCAAAACAGACCCTGcT CTACGCAAAACAGACCCTGcT gTcccag gcggccgc
Claims (70)
- センス鎖及びアンチセンス鎖を含むGST-πの発現を阻害する核酸分子であって、前記鎖が二重鎖領域を形成し、前記アンチセンス鎖が配列番号157であり、前記センス鎖が配列番号131である核酸分子。
- 前記二重鎖領域内の1つ以上のヌクレオチドが修飾又は化学的修飾されている、請求項1記載の核酸分子。
- 前記修飾又は化学的修飾ヌクレオチドが、2’-デオキシヌクレオチド、2’-O-アルキル置換ヌクレオチド、2’-デオキシ-2’-フルオロ置換ヌクレオチド、ホスホロチオエートヌクレオチド、ロックドヌクレオチド又はそれらの任意の組み合わせである、請求項2記載の核酸分子。
- 前記アンチセンス鎖が複数の位置にデオキシヌクレオチドを有し、前記複数の位置が以下のうちの1つである、請求項2記載の核酸分子。
アンチセンス鎖の5’末端からの位置4、6及び8のそれぞれ;
アンチセンス鎖の5’末端からの位置3、5及び7のそれぞれ;
アンチセンス鎖の5’末端からの位置1、3、5及び7のそれぞれ;
アンチセンス鎖の5’末端からの位置3〜8のそれぞれ;又は
アンチセンス鎖の5’末端からの位置5〜8のそれぞれ - 前記分子が、前記二重鎖領域内に1つ以上の2'-デオキシ-2'-フルオロ置換ヌクレオチドを有する、請求項4記載の核酸分子。
- 前記アンチセンス鎖が配列番号182であり、前記センス鎖が配列番号156である、請求項2記載の核酸分子。
- 前記アンチセンス鎖が配列番号180であり、前記センス鎖が配列番号154である、請求項2記載の核酸分子。
- 前記アンチセンス鎖が配列番号181であり、前記センス鎖が配列番号155である、請求項2記載の核酸分子。
- 前記分子が、50pM未満のIC50でGST-πmRNAの発現を阻害する、請求項1〜8いずれか1項記載の核酸分子。
- 前記分子の単回投与が、インビボにおいてGST-πmRNAの発現レベルを少なくとも25%にまで阻害する、請求項1〜8いずれか1項記載の核酸分子。
- 前記パッセンジャー鎖が少なくとも50倍減少したオフターゲット活性を有する、請求項1〜8いずれか1項記載の核酸分子。
- 請求項1〜8いずれか1項記載の核酸分子及び薬学的に許容される担体を含む医薬組成物。
- 前記担体が脂質分子又はリポソームを含む、請求項12記載の医薬組成物。
- 請求項1〜8いずれか1項記載の核酸分子を含むベクター又は細胞。
- 必要とする被験体に請求項12記載の組成物を投与することを含む、GST-π発現に関連する疾患を治療する方法であって、当該疾患が悪性腫瘍、癌、突然変異KRASを発現する細胞に起因する癌、肉腫又は癌腫である方法。
- センス鎖及びアンチセンス鎖を含むGST-πの発現を阻害する核酸分子であって、前記鎖が二重鎖領域を形成し、前記アンチセンス鎖が配列番号195であり、前記センス鎖が配列番号183である核酸分子。
- 前記二重鎖領域の1つ以上のヌクレオチドが修飾又は化学的修飾されている、請求項16記載の核酸分子。
- 前記修飾又は化学的修飾ヌクレオチドが、2’-デオキシヌクレオチド、2’-O-アルキル置換ヌクレオチド、2’-デオキシ-2’-フルオロ置換ヌクレオチド、ホスホロチオエートヌクレオチド、ロックドヌクレオチド又はそれらの任意の組み合わせである、請求項17記載の核酸分子。
- 前記アンチセンス鎖が複数の位置にデオキシヌクレオチドを有し、前記複数の位置が以下のうちの1つである、請求項17記載の核酸分子。
アンチセンス鎖の5’末端からの位置4、6及び8のそれぞれ;
アンチセンス鎖の5’末端からの位置3、5及び7のそれぞれ;
アンチセンス鎖の5’末端からの位置1、3、5及び7のそれぞれ;
アンチセンス鎖の5’末端からの位置3〜8のそれぞれ;又は
アンチセンス鎖の5’末端からの位置5〜8のそれぞれ - 前記分子が、前記二重鎖領域内に1つ以上の2'-デオキシ-2'-フルオロ置換ヌクレオチドを有する、請求項19記載の核酸分子。
- 前記アンチセンス鎖が配列番号205であり、前記センス鎖が配列番号193である、請求項17記載の核酸分子。
- 前記アンチセンス鎖が配列番号202であり、前記センス鎖が配列番号190である、請求項17記載の核酸分子。
- 前記アンチセンス鎖が配列番号199であり、前記センス鎖が配列番号187である、請求項17記載の核酸分子。
- 前記アンチセンス鎖が配列番号201であり、前記センス鎖が配列番号189である、請求項17記載の核酸分子。
- 前記分子が、50pM未満のIC50でGST-πmRNAの発現を阻害する、請求項16〜24いずれか1項記載の核酸分子。
- 前記分子の単回投与が、インビボにおいてGST-πmRNAの発現レベルを少なくとも25%にまで阻害する、請求項16〜24いずれか1項記載の核酸分子。
- 前記パッセンジャー鎖が少なくとも50倍減少したオフターゲット活性を有する、請求項16〜24いずれか1項記載の核酸分子。
- 請求項16〜24いずれか1項記載の核酸分子及び薬学的に許容される担体を含む医薬組成物。
- 前記担体が脂質分子又はリポソームを含む、請求項28記載の医薬組成物。
- 請求項16〜24いずれか1項記載の核酸分子を含むベクター又は細胞。
- 必要とする被験体に請求項28記載の組成物を投与することを含む、GST-π発現に関連する疾患を治療する方法であって、当該疾患が悪性腫瘍、癌、突然変異KRASを発現する細胞に起因する癌、肉腫又は癌腫である方法。
- センス鎖及びアンチセンス鎖を含むGST-πの発現を阻害する核酸分子であって、前記鎖が二重鎖領域を形成し、前記アンチセンス鎖が配列番号222であり、前記センス鎖が配列番号207である核酸分子。
- 前記二重鎖領域の1つ以上のヌクレオチドが修飾又は化学的修飾されている、請求項32記載の核酸分子。
- 前記修飾又は化学的修飾ヌクレオチドが、2’-デオキシヌクレオチド、2’-O-アルキル置換ヌクレオチド、2’-デオキシ-2’-フルオロ置換ヌクレオチド、ホスホロチオエートヌクレオチド、ロックドヌクレオチド又はそれらの任意の組み合わせである、請求項33記載の核酸分子。
- 前記アンチセンス鎖が複数の位置にデオキシヌクレオチドを有し、前記複数の位置が以下のうちの1つである、請求項33記載の核酸分子。
アンチセンス鎖の5’末端からの位置4、6及び8のそれぞれ;
アンチセンス鎖の5’末端からの位置3、5及び7のそれぞれ;
アンチセンス鎖の5’末端からの位置1、3、5及び7のそれぞれ;
アンチセンス鎖の5’末端からの位置3〜8のそれぞれ;又は
アンチセンス鎖の5’末端からの位置5〜8のそれぞれ - 前記分子が、前記二重鎖領域内に1つ以上の2'-デオキシ-2'-フルオロ置換ヌクレオチドを有する、請求項35記載の核酸分子。
- 前記アンチセンス鎖が配列番号232であり、前記センス鎖が配列番号217である、請求項33記載の核酸分子。
- 前記分子が、50pM未満のIC50でGST-πmRNAの発現を阻害する、請求項32〜37いずれか1項記載の核酸分子。
- 前記分子の単回投与が、インビボにおいてGST-πmRNAの発現レベルを少なくとも25%にまで阻害する、請求項32〜37いずれか1項記載の核酸分子。
- 前記パッセンジャー鎖が少なくとも50倍減少したオフターゲット活性を有する、請求項32〜37いずれか1項記載の核酸分子。
- 請求項32〜37いずれか1項記載の核酸分子及び薬学的に許容される担体を含む医薬組成物。
- 前記担体が脂質分子又はリポソームを含む、請求項41記載の医薬組成物。
- 請求項32〜37いずれか1項記載の核酸分子を含むベクター又は細胞。
- 必要とする被験体に請求項41記載の組成物を投与することを含む、GST-π発現に関連する疾患を治療する方法であって、当該疾患が悪性腫瘍、癌、突然変異KRASを発現する細胞に起因する癌、肉腫又は癌腫である方法。
- センス鎖及びアンチセンス鎖を含むGST-πの発現を阻害する核酸分子であって、前記鎖が二重鎖領域を形成し、前記アンチセンス鎖が配列番号249であり、前記センス鎖が配列番号237であり、前記二重鎖領域の1つ以上のヌクレオチドが修飾又は化学的修飾されている核酸分子。
- 前記修飾又は化学的修飾ヌクレオチドが、2’-デオキシヌクレオチド、2’-O-アルキル置換ヌクレオチド、2’-デオキシ-2’-フルオロ置換ヌクレオチド、ホスホロチオエートヌクレオチド、ロックドヌクレオチド又はそれらの任意の組み合わせである、請求項45記載の核酸分子。
- 前記アンチセンス鎖が複数の位置にデオキシヌクレオチドを有し、前記複数の位置が以下のうちの1つである、請求項45記載の核酸分子。
アンチセンス鎖の5’末端からの位置4、6及び8のそれぞれ;
アンチセンス鎖の5’末端からの位置3、5及び7のそれぞれ;
アンチセンス鎖の5’末端からの位置1、3、5及び7のそれぞれ;
アンチセンス鎖の5’末端からの位置3〜8のそれぞれ;又は
アンチセンス鎖の5’末端からの位置5〜8のそれぞれ - 前記分子が、前記二重鎖領域内に1つ以上の2'-デオキシ-2'-フルオロ置換ヌクレオチドを有する、請求項47記載の核酸分子。
- 前記アンチセンス鎖が配列番号255であり、前記センス鎖が配列番号243である、請求項45記載の核酸分子。
- 前記アンチセンス鎖が配列番号256であり、前記センス鎖が配列番号244である、請求項45記載の核酸分子。
- 前記分子が、200pM未満のIC50でGST-πmRNAの発現を阻害する、請求項45〜50いずれか1項記載の核酸分子。
- 前記分子の単回投与が、インビボにおいてGST-πmRNAの発現レベルを少なくとも25%にまで阻害する、請求項45〜50いずれか1項記載の核酸分子。
- 前記パッセンジャー鎖が少なくとも50倍減少したオフターゲット活性を有する、請求項45〜50いずれか1項記載の核酸分子。
- 請求項45〜50いずれか1項記載の核酸分子及び薬学的に許容される担体を含む医薬組成物。
- 前記担体が脂質分子又はリポソームを含む、請求項54記載の医薬組成物。
- 請求項45〜50いずれか1項記載の核酸分子を含むベクター又は細胞。
- 必要とする被験体に請求項54記載の組成物を投与することを含む、GST-π発現に関連する疾患を治療する方法であって、当該疾患が悪性腫瘍、癌、突然変異KRASを発現する細胞に起因する癌、肉腫又は癌腫である方法。
- センス鎖及びアンチセンス鎖を含むGST-πの発現を阻害する核酸分子であって、前記鎖が二重鎖領域を形成し、前記アンチセンス鎖が配列番号273であり、前記センス鎖が配列番号261であり、前記二重鎖領域の1つ以上のヌクレオチドが修飾又は化学的修飾されている核酸分子。
- 前記修飾又は化学的修飾ヌクレオチドが、2’-デオキシヌクレオチド、2’-O-アルキル置換ヌクレオチド、2’-デオキシ-2’-フルオロ置換ヌクレオチド、ホスホロチオエートヌクレオチド、ロックドヌクレオチド又はそれらの任意の組み合わせである、請求項58記載の核酸分子。
- 前記アンチセンス鎖が複数の位置にデオキシヌクレオチドを有し、前記複数の位置が以下のうちの1つである、請求項58記載の核酸分子。
アンチセンス鎖の5’末端からの位置4、6及び8のそれぞれ;
アンチセンス鎖の5’末端からの位置3、5及び7のそれぞれ;
アンチセンス鎖の5’末端からの位置1、3、5及び7のそれぞれ;
アンチセンス鎖の5’末端からの位置3〜8のそれぞれ;又は
アンチセンス鎖の5’末端からの位置5〜8のそれぞれ - 前記分子が、前記二重鎖領域内に1つ以上の2'-デオキシ-2'-フルオロ置換ヌクレオチドを有する、請求項60記載の核酸分子。
- 前記アンチセンス鎖が配列番号277であり、前記センス鎖が配列番号265である、請求項58記載の核酸分子。
- 前記アンチセンス鎖が配列番号280であり、前記センス鎖が配列番号268である、請求項58記載の核酸分子。
- 前記分子が、300pM未満のIC50でGST-πmRNAの発現を阻害する、請求項58〜63いずれか1項記載の核酸分子。
- 前記分子の単回投与が、インビボにおいてGST-πmRNAの発現レベルを少なくとも25%にまで阻害する、請求項58〜63いずれか1項記載の核酸分子。
- 前記パッセンジャー鎖が少なくとも50倍減少したオフターゲット活性を有する、請求項58〜63いずれか1項記載の核酸分子。
- 請求項58〜63いずれか1項記載の核酸分子及び薬学的に許容される担体を含む医薬組成物。
- 前記担体が脂質分子又はリポソームを含む、請求項67記載の医薬組成物。
- 請求項58〜63いずれか1項記載の核酸分子を含むベクター又は細胞。
- 必要とする被験体に請求項67記載の組成物を投与することを含む、GST-π発現に関連する疾患を治療する方法であって、当該疾患が悪性腫瘍、癌、突然変異KRASを発現する細胞に起因する癌、肉腫又は癌腫である方法。
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