JP2013535982A - 内部非核酸スペーサーを含む一本鎖RNAi剤関連出願の相互参照本出願は、2010年8月24日に出願された米国特許仮出願第61/376,471号の恩典を主張し、該仮出願は引用により本明細書に組み込まれる。 - Google Patents
内部非核酸スペーサーを含む一本鎖RNAi剤関連出願の相互参照本出願は、2010年8月24日に出願された米国特許仮出願第61/376,471号の恩典を主張し、該仮出願は引用により本明細書に組み込まれる。 Download PDFInfo
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Abstract
【選択図】図9
Description
(a)2つ以上のヌクレオチド部分を含む核酸部分、および(b)1つ以上の非ヌクレオチドスペーサー部分を含む内部(「末端」と対照的)スペーサー部分を含み、該非ヌクレオチドスペーサー部分が該分子の2つのヌクレオチド部分を共有結合によって連結している一本鎖RNA分子を提供する。本発明の一本鎖RNA分子のヌクレオチド部分は互いに相補的でなく、したがって、前記部分は塩基対を形成しない。本発明の一本鎖RNA分子は、RNA干渉機構によって遺伝子発現を阻害し得るガイド鎖またはアンチセンス鎖としての機能を果たすものであり、したがって一本鎖RNAi剤である。
本出願書類で用いる場合、以下の専門用語および定義を適用する。
本開示により、少なくとも1つの内部非ヌクレオチドスペーサーを含む一本鎖RNA分子であって、該スペーサーにより該分子の2つのヌクレオチド部分が連結されて一体になっている一本鎖RNA分子を提供する。したがって、本発明の一本鎖RNA分子は連続したヌクレオチド鎖ではなく、1つ以上の非ヌクレオチドスペーサーによって分断された1つより多くのヌクレオチド部分を含むものであり、該ヌクレオチド部分は1個以上のヌクレオチド、非ヌクレオチド代替部分またはその組合せを含むものである。本発明の一本鎖RNA分子は、RNA干渉機構によって遺伝子発現を阻害し得るガイド鎖またはアンチセンス鎖としての機能を果たし、したがってRNAi剤である。本発明の一本鎖RNAi分子は、細胞内の1つ以上のRNA標的部位に一部、実質的に、または完璧に相補的な配列を含むものである。
式III:
5’ N1−S1−N2 3’
で表される、または示されるものであり得、
式中、N1は、第1のヌクレオチド部分を表し、1個のヌクレオチドまたは連続ヌクレオチド鎖のいずれかからなり;S1は、非ヌクレオチドスペーサー部分を表し、1つ以上の非ヌクレオチドスペーサーからなり;N2は、第2のヌクレオチド部分を表し、1個のヌクレオチドまたは連続ヌクレオチド鎖のいずれかからなる。N1とN2内のヌクレオチドの総数は、8〜26個(例えば、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25または26個)のヌクレオチドであり、該分子の少なくとも8個のヌクレオチドが標的RNA内の標的部位と塩基対形成し得る。N1とN2内の「ヌクレオチド(1個または複数)」は、ヌクレオチド、修飾ヌクレオチド、ヌクレオチド類似体もしくは非ヌクレオチド代替部分のいずれか、またはその組合せである。一実施形態において、個々に、N1およびN2は1〜25個のヌクレオチドからなるものであり得、ここで、N1とN2の和は8〜26個(例えば、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25または26個)のヌクレオチドである。N1とN2は自己相補的でなく、したがって、互いの実質的な塩基対形成に関与し得ない。該分子の連続ヌクレオチド鎖において、ヌクレオチドは、ホスホジエステル結合および/または非ホスホジエステル接続部によって接続されている。スペーサー部分(S1)は、共有結合によって、該分子の第1のヌクレオチド部分(N1)の3’末端ヌクレオチドと第2のヌクレオチド部分(N2)の5’末端ヌクレオチドに結合されている。例えば、該スペーサー部分は、隣接ヌクレオチドの遊離リン酸基にホスホジエステル結合によって結合された1つ以上のホスホルアミダイトスペーサーを含むものであってもよい。該分子のスペーサー部分(S1)は、単一の非ヌクレオチドスペーサーからなるものであってもよく、連結されて一体になった1つより多くの非ヌクレオチドスペーサーからなるものであってもよい。該分子のS1部分内に1つより多くの非ヌクレオチドスペーサーが存在する場合、スペーサーは同じである(すなわち、同じ構造を有する)か、または異なっている(すなわち、異なる構造を有する)かのいずれかであり得る。2つの非ヌクレオチドスペーサーが該分子のS1部分内で連結されている場合、各スペーサーは、共有結合によって、それぞれ該分子のN1部分とN2部分内の1個のヌクレオチドに結合されている。3つの非ヌクレオチドスペーサーが該オリゴヌクレオチドのS1部分内で連続的に連結されている場合、内部(第2の)スペーサーは、該分子のN1部分またはN2部分のどちらとも共有結合を形成しない。その代わり、該内部スペーサーは、共有結合によって第1および第3のスペーサーに結合され、これらを連結して一体にする。
5’ N1−S1−N2−S2−N3 3’
で表される、または示されるものであり得、
式中、N1は、第1のヌクレオチド部分を表し、1個のヌクレオチドまたは連続ヌクレオチド鎖のいずれかからなり;S1は、第1の非ヌクレオチドスペーサー部分を表し、1つ以上の非ヌクレオチドスペーサーからなり;N2は、第2のヌクレオチド部分を表し、1個のヌクレオチドまたは連続ヌクレオチド鎖のいずれかからなり;S2は、第2の非ヌクレオチド内部スペーサー部分を表し、1つ以上の非ヌクレオチドスペーサーからなり;N3は、第3のヌクレオチド部分を表し、1個のヌクレオチドまたは連続ヌクレオチド鎖のいずれかからなる。一実施形態において、N1、N2およびN3内のヌクレオチドの総数は8〜約26個(例えば、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25または26個)のヌクレオチドであり、該分子の少なくとも8個のヌクレオチドが標的RNA内の標的部位と塩基対形成し得る。N1、N2およびN3内の「ヌクレオチド(1個または複数)」は、ヌクレオチド、修飾ヌクレオチド、ヌクレオチド類似体もしくは非ヌクレオチド代替部分のいずれか、またはその組合せである。一実施形態において、個々に、該ヌクレオチド部分(N1、N2、N3)は1〜24個のヌクレオチドからなるものであり得、ここで、該分子内のヌクレオチドの合計は8〜26個のヌクレオチドである。該RNAi分子のヌクレオチド部分は自己相補的でなく、したがって、互いとの実質的な塩基対形成に関与し得ない。各連続ヌクレオチド鎖において、ヌクレオチドは、ホスホジエステル結合および/または非ホスホジエステル接続部によって接続されている。該スペーサー部分は、共有結合によって該分子のヌクレオチド部分の末端ヌクレオチドに結合されている。一実施形態において、該スペーサー部分は、隣接ヌクレオチドの遊離リン酸基にホスホジエステル結合によって結合された1つ以上のホスホルアミダイトスペーサーを含むものである。該分子の各スペーサー部分は、単一の非ヌクレオチドスペーサーからなるものであってもよく、連結されて一体になった1つより多くの非ヌクレオチドスペーサーからなるものであってもよい。該分子のスペーサー部分内に1つより多くの非ヌクレオチドスペーサーが存在する場合、スペーサーは同じである(すなわち、同じ構造を有する)か、または異なっている(すなわち、異なる構造を有する)かのいずれかであり得る。2つの非ヌクレオチドスペーサーが該分子のスペーサー部分内で連結されている場合、各スペーサーは、共有結合によって、該分子の隣接ヌクレオチド部分内の末端ヌクレオチドに結合されている。3つの非ヌクレオチドスペーサーが該分子のスペーサー部分内で連続的に連結されている場合、内部(第2の)スペーサーは該分子のヌクレオチド部分と共有結合を形成しない。その代わり、該内部スペーサーは、共有結合によって第1および第3のスペーサーに結合され、これらを連結して一体にする。
置換ヌクレオチドおよび修飾ヌクレオチドを本発明の一本鎖RNAi分子に導入することにより、外来的に送達される天然RNA分子(すなわち、標準ヌクレオチドを有する)に固有のインビボ安定性およびバイオアベイラビリティの潜在的限界を克服するためのツールが提供される。一部の特定の実施形態において、本開示の置換型または修飾型一本鎖RNAi分子の使用により、この分子は被検体または生物学的試料中(例えば、血清中)において半減期が増大するように設計されたものであり得るため、低用量で所与の治療効果の達成が可能となり得る。さらに、特定の細胞もしくは組織を標的化することによって、または一本鎖RNAi分子の細胞内取込みを改善することによって、一本鎖RNAi分子のバイオアベイラビリティを改善するために特定の置換または修飾が使用され得る。したがって、本開示の一本鎖RNAi分子の活性が、同じ構造の非修飾型または非置換型RNAi分子と比べていくぶん低い場合であっても(例えば、約20%未満または30%未満またはさらに40%未満)、置換型または修飾型RNAi分子の全体活性は、該分子の改善された安定性または送達により、その天然対応物よりも大きくなり得る。また、置換型およびまたは修飾型一本鎖RNAi分子により、例えばヒトにおいてインターフェロン応答が活性化される可能性が最小限となり得る。
D.一本鎖RNAi分子の合成
本開示の例示的な分子は当業者に知られたいくつかの手法を用いて得ることができる。例えば、本発明のRNAi分子は、化学合成されるもの、組換え産生される(例えば、プラスミドにコードされる)もの、またはその組合せであり得る。
本明細書に記載のように、本発明の一本鎖RNA分子は、RNAi機構によって標的配列の発現を阻害し得るものである。一実施形態において、該一本鎖RNAi分子は、所望のノックダウン機能を有する事前に特定されたRNAi剤(例えば、siRNA、miRNA)を基にして設計され得る。例えば、本発明の一本鎖RNAi分子がmiRNA模倣物である場合、これは、天然に存在する対応miRNA分子(表1参照)またはその類似体(例えば、化学修飾形態)から得られる。本出願の出願日の時点で、さまざまな種に内在性の3000種類を超えるmiRNA分子が公衆に利用可能なデータベースにおいて知得され得る(例えば、公衆に利用可能なmiRBase配列データベースを参照のこと(Griffith−Jonesら,2004,Nucleic Acids Research 32:D109−D111およびGriffith−Jonesら,2006,Nucleic Acids Research 34:D140−D144に記載,ワールドワイドウェブにおいてWellcome Trust Sanger Instituteのウェブサイトでアクセス可能)。本明細書の表1に、1090種類の成熟ヒトmiRNA配列の一覧(配列番号:1〜1090)を示している。別の例では、本発明の一本鎖RNAi分子は、選択した標的配列の発現を阻害することがわかっているか、または標的mRNA配列の発現を阻害する潜在性を有するかのいずれかである事前に特定されたsiRNAから得られ得る。具体的には、事前に特定されたRNAi分子(すなわち、参照RNAi分子)から得られる一本鎖RNAi分子は、1つ以上の内部非ヌクレオチドスペーサー部分を参照RNAi分子のガイド鎖内に導入することにより設計され得る。別の実施形態では、該一本鎖RNAi分子は、特定の標的配列の発現をノックダウンする目的のためにデノボ設計され得る(すなわち、既知のRNAi剤を基にしない)。
本明細書に示すように、本発明の一本鎖RNA分子は、好ましくは細胞内RNAi経路に関与し得る、あるいは同じまたは関連経路をモジュレートして病的または疾患状態と関連している標的遺伝子の阻害をもたらし得るRNAi剤である。miRNA模倣物である一本鎖RNA分子の場合、該ssRNAi分子は、レベルの低下あるいはレベルが不適切に低いことが病的または疾患状態と関連している天然に存在する対応miRNAが補足されるように、または置き換えられるように設計される。したがって、本発明の一本鎖RNAi分子は、さまざまな治療的、診断的、標的確認、ゲノム知得、遺伝子操作および薬理ゲノミクスの適用用途のための方法において使用され得る有用な試薬である。
本開示は、保存または投与のために調製される一本鎖RNAi分子組成物であって、医薬有効量の所望のRNAi分子を薬学的に許容され得る担体または希釈剤中に含む一本鎖RNAi分子組成物を含む。本開示の一本鎖RNAi分子組成物は薬学的に許容され得る製剤として有効に使用され得る。薬学的に許容され得る製剤は、被検体の疾患状態または他の有害な病状を予防、その発症もしくは重症度を改変、または該疾患状態または該病状を処置(1つ以上の症状を検出可能もしくは測定可能な程度まで緩和する)するものである。したがって、医薬組成物または製剤は、細胞内または被検体(ヒトなど)への投与(例えば、全身投与)に適した形態の組成物または製剤をいう。本発明の開示の医薬組成物は、内包された一本鎖RNAi分子(1種類または複数種)が被検体に投与するとバイオアベイラブルとなることが可能なように製剤化される。
一態様において、本発明は、本明細書に記載の一本鎖RNAi分子を内包する担体系を提供する。一部の実施形態において、担体系は、脂質系担体系、カチオン性脂質もしくはリポソーム核酸複合体、リポソーム、ミセル、ビロソーム、脂質ナノ粒子またはその混合物である。他の実施形態では、担体系は、ポリマー系担体系(カチオン性ポリマー−核酸複合体など)である。さらなる実施形態では、担体系は、シクロデキストリン系担体系(シクロデキストリンポリマー−核酸複合体など)である。さらなる実施形態において、担体系は、タンパク質系担体系(カチオン性ペプチド−核酸複合体など)である。好ましくは、担体系は脂質ナノ粒子(「LNP」)製剤である(in)。
本発明の一本鎖RNAi分子(置換されていても修飾されていてもコンジュゲートされていてもよい)、その組成物、および本発明の開示の方法を用いた処置に適した被検体(例えば、哺乳動物の、ヒト)としては、少なくとも一部において標的遺伝子もしくは配列の異常な発現レベルによって媒介される1つ以上の疾患もしくは病状に苦しんでいる被検体、標的遺伝子/配列の異常レベルによって引き起こされる疾患もしくは該異常レベルと関連している疾患を発症するリスクがある被検体、または対応するssRNAi分子によって媒介されるRNAiレベルを補足もしくは増大させることによる処置に適した被検体が挙げられる(例えば、過剰増殖性(例えば、がん)、血管形成性、代謝性または炎症性(例えば、関節炎)の疾患または障害または病状)。
RT−qPCRアッセイ−HCT−116細胞を、10%ウシ胎仔血清と1%ペニシリン−ストレプトマイシンを補給したMcCoy’s 5A Medium(Mediatech Inc.)中で培養した。この細胞を96ウェル培養プレート内で、6000細胞/ウェルの密度で24時間平板培養した後、トランスフェクションした。
RT−qPCRアッセイ(一次スクリーニングおよび用量応答曲線)−Hepal−6細胞を、10%ウシ胎仔血清、1%ペニシリン−ストレプトマイシンおよび1%重炭酸ナトリウムを補給したダルベッコ改変イーグル培地中で培養した。この細胞を96ウェル培養プレート内で、3000細胞/ウェルの密度で24時間平板培養した後、トランスフェクションした。
Claims (22)
- 標的RNAに対するRNA干渉を媒介する一本鎖RNA分子であって、前記一本鎖RNAが:
(a)自己相補的でない第1のヌクレオチド部分(N1)と第2のヌクレオチド部分(N2)を含む核酸部分(ここで、当該核酸部分は、標的RNAの標的部位と塩基対形成し得る少なくとも8個のヌクレオチドを含むものであり、該核酸部分内のヌクレオチドの総数は8〜26ヌクレオチドである);および、
(i)内部スペーサー部分(ここで、当該スペーサー部分は、第1のヌクレオチド部分と第2のヌクレオチド部分を共有結合によって連結する少なくとも第1の非ヌクレオチドスペーサー部分(S1)を含むものである)、
を含む一本鎖RNA分子。 - 下記の構造:
5’ N1−S1−N2 3’
を含むものであり、
式中:
(a)N1は、1個のヌクレオチドまたは連続ヌクレオチド鎖のいずれかを含むものであり;
(b)S1は、N1とN2を共有結合によって連結する1つ以上の非ヌクレオチドスペーサーを含むものであり;
(c)N2は、1個のヌクレオチドまたは連続ヌクレオチド鎖のいずれかを含むものである、
請求項1に記載の分子。 - S1が脂肪族または芳香族の有機基である、請求項1または2に記載の分子。
- S1が、置換されていてもよいC1〜C12アルキル鎖である、請求項1〜3のいずれか一項に記載の分子。
- 前記アルキル鎖がコレステロールで置換されていてもよい、請求項4に記載の分子。
- S1が、C3アルキル、C6アルキルおよびポリエチレングリコールからなる群より選択される、請求項1〜5のいずれか一項に記載の分子。
- N1が13〜20ヌクレオチド長である、請求項1〜6のいずれか一項に記載の分子。
- 前記核酸部分内のヌクレオチドの総数が約19〜約21ヌクレオチドである、請求項1〜7のいずれか一項に記載の分子。
- 前記標的部位が前記標的RNAの非翻訳領域内に存在している、請求項1〜8のいずれか一項に記載の分子。
- 前記標的部位と塩基対形成し得る少なくとも8個のヌクレオチドが、天然に存在する内在性miRNAヌクレオチド配列のシード配列の全体または一部である、請求項9に記載の分子。
- S1が、前記天然に存在する内在性miRNAヌクレオチド配列の1〜4個の内部ヌクレオチドと置き換えられたものである、請求項10に記載の分子。
- 前記分子の核酸部分が、前記天然に存在する内在性miRNAヌクレオチド配列と少なくとも50%相同である、請求項9〜11のいずれか一項に記載の分子。
- 前記標的部位が前記標的RNAの遺伝子コード領域に存在している、請求項1〜8のいずれか一項に記載の分子。
- 前記分子の核酸部分が前記標的部位に少なくとも90%相補的である、請求項1〜13のいずれか一項に記載の分子。
- 前記核酸部分が、前記標的部位と塩基対形成し得る少なくとも20個のヌクレオチドを含むものである、請求項1〜14のいずれか一項に記載の分子。
- 前記核酸部分が、さらに第3のヌクレオチド部分(N3)を含むものであり、前記内部スペーサー部分が、さらに第2の非ヌクレオチドスペーサー部分(S2)を含むものである、請求項1〜15のいずれか一項に記載の分子。
- 少なくとも1個のヌクレオチドが修飾糖鎖を有する、請求項1〜16のいずれか一項に記載の分子。
- 少なくとも1個のヌクレオチドが修飾ヌクレオシド間結合を有する、請求項1〜17のいずれか一項に記載の分子。
- 5’末端、3’末端、または5’末端と3’末端の両方に末端キャップを有する、請求項1〜18のいずれか一項に記載の分子。
- 請求項1〜19のいずれか一項に記載の一本鎖RNA分子および薬学的に許容され得る担体を含む組成物。
- リポソーム、ヒドロゲル、シクロデキストリン、生分解性ナノカプセル、生体接着性ミクロスフィアまたはタンパク質性ベクターをさらに含む、請求項20に記載の組成物。
- 請求項20または請求項21に記載の組成物を投与することを含む、細胞内の内在性RNA標的遺伝子の発現を低減させる方法。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017502665A (ja) * | 2013-12-17 | 2017-01-26 | インコドゥヂュン シーオー.,エルティーディー | オフターゲットを防ぐために変形したrna干渉誘導拡散およびその用途 |
JPWO2015190584A1 (ja) * | 2014-06-12 | 2017-04-20 | 東レ株式会社 | 前立腺がんの検出キット又はデバイス及び検出方法 |
US11535899B2 (en) | 2018-08-10 | 2022-12-27 | Toray Industries, Inc. | Kit, device and method for detecting prostate cancer |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9181551B2 (en) | 2002-02-20 | 2015-11-10 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US9657294B2 (en) | 2002-02-20 | 2017-05-23 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US8748405B2 (en) * | 2007-01-26 | 2014-06-10 | City Of Hope | Methods and compositions for the treatment of cancer or other diseases |
US9096850B2 (en) | 2009-08-24 | 2015-08-04 | Sirna Therapeutics, Inc. | Segmented micro RNA mimetics |
EP3372684B1 (en) * | 2010-08-24 | 2020-10-07 | Sirna Therapeutics, Inc. | Single-stranded rnai agents containing an internal, non-nucleic acid spacer |
EP3766975A1 (en) | 2010-10-29 | 2021-01-20 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of gene expression using short interfering nucleic acid (sina) |
SG190355A1 (en) | 2010-12-15 | 2013-07-31 | Miragen Therapeutics | Microrna inhibitors comprising locked nucleotides |
US9428749B2 (en) | 2011-10-06 | 2016-08-30 | The Board Of Regents, The University Of Texas System | Control of whole body energy homeostasis by microRNA regulation |
US20150299696A1 (en) * | 2012-05-02 | 2015-10-22 | Sirna Therapeutics, Inc. | SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS |
US9334498B2 (en) | 2012-05-10 | 2016-05-10 | Uab Research Foundation | Methods and compositions for modulating MIR-204 activity |
US20140378526A1 (en) * | 2012-05-11 | 2014-12-25 | City Of Hope | Design of nucleic acid binding molecules with non-watson crick and non-canonical pairing based on artificial mutation consensus sequences to counter escape mutations |
EP3747891A3 (en) * | 2012-05-21 | 2021-03-24 | Agilent Technologies, Inc. | Compositions and methods for conjugating oligonucleotides |
EP2859103B1 (en) | 2012-06-06 | 2019-04-17 | Boehringer Ingelheim International GmbH | CELL ENGINEERING USING RNAs |
US9388408B2 (en) | 2012-06-21 | 2016-07-12 | MiRagen Therapeutics, Inc. | Oligonucleotide-based inhibitors comprising locked nucleic acid motif |
WO2015050871A2 (en) * | 2013-10-04 | 2015-04-09 | Novartis Ag | Organic compounds to treat hepatitis b virus |
CA2925129C (en) | 2013-10-04 | 2023-04-04 | Novartis Ag | 3' end caps for rnai agents for use in rna interference |
CN104560992B (zh) * | 2013-10-10 | 2018-01-02 | 复旦大学附属妇产科医院 | 一种用于预防和治疗人乳头瘤病毒感染和宫颈癌的微小rna |
WO2015106255A1 (en) | 2014-01-13 | 2015-07-16 | City Of Hope | Multivalent oligonucleotide assemblies |
CN103924002B (zh) * | 2014-05-04 | 2016-01-20 | 山东大学 | 血清中的microRNA作为肝癌诊断标志物的应用 |
KR20170103841A (ko) | 2015-01-20 | 2017-09-13 | 미라젠 세러퓨틱스 인코포레이티드 | Mir-92 억제제 및 이의 용도 |
EP3337900B1 (en) | 2015-08-20 | 2021-04-07 | Asociación Centro de Investigación Cooperativa en Biociencias - CIC bioGUNE | Methods and compositions to treat liver diseases and conditions |
TWI685500B (zh) * | 2015-10-13 | 2020-02-21 | 長庚大學 | 以微核酸-520b(miR-520b)序列作爲抑制頭頸癌腫瘤生長、侵犯與轉移及其醫藥組成物之用途 |
CA3007984A1 (en) * | 2015-12-08 | 2017-06-15 | Solstice Biologics, Ltd. | Polynucleotide constructs having an auxiliary moiety non-bioreversibly linked to an internucleoside phosphate or phosphorothioate |
WO2017181088A1 (en) * | 2016-04-14 | 2017-10-19 | University Of Florida Research Foundation, Incorporated | Use of mir-223-3p as a cancer therapeutic and method for treating cancer using the same |
CN105861728A (zh) * | 2016-06-12 | 2016-08-17 | 上海市第十人民医院 | 循环miRNA作为年龄相关黄斑变性诊断标志物中的应用 |
CN107630015B (zh) * | 2016-07-19 | 2021-03-09 | 上海市东方医院 | 一种稳定的dna-rna双链结构 |
AU2017368050A1 (en) | 2016-11-29 | 2019-06-20 | Puretech Lyt, Inc. | Exosomes for delivery of therapeutic agents |
WO2019006455A1 (en) | 2017-06-30 | 2019-01-03 | Solstice Biologics, Ltd. | AUXILIARIES OF CHIRAL PHOSPHORAMIDITIS AND METHODS OF USE THEREOF |
CN112513272A (zh) * | 2018-05-31 | 2021-03-16 | 高丽大学校产学协力团 | 抑制微小rna的修饰核酸及其用途 |
CN109706239A (zh) * | 2018-09-26 | 2019-05-03 | 南京市妇幼保健院 | 一种miR-1976在防治细菌性阴道病中的应用 |
WO2023178144A2 (en) | 2022-03-16 | 2023-09-21 | Empirico Inc. | Galnac compositions for improving sirna bioavailability |
CN114767703B (zh) * | 2022-06-20 | 2022-09-02 | 山东恺悌生物制品有限公司 | miR-4311模拟物在制备肺癌治疗药物中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004014933A1 (en) * | 2002-08-07 | 2004-02-19 | University Of Massachusetts | Compositions for rna interference and methods of use thereof |
WO2006102970A2 (en) * | 2005-03-08 | 2006-10-05 | Qiagen Gmbh | Modified short interfering rna |
US20080311040A1 (en) * | 2007-03-06 | 2008-12-18 | Flagship Ventures | METHODS AND COMPOSITIONS FOR IMPROVED THERAPEUTIC EFFECTS WITH siRNA |
Family Cites Families (198)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3687808A (en) | 1969-08-14 | 1972-08-29 | Univ Leland Stanford Junior | Synthetic polynucleotides |
WO1991003162A1 (en) | 1989-08-31 | 1991-03-21 | City Of Hope | Chimeric dna-rna catalytic sequences |
US5495009A (en) | 1989-10-24 | 1996-02-27 | Gilead Sciences, Inc. | Oligonucleotide analogs containing thioformacetal linkages |
US5264562A (en) | 1989-10-24 | 1993-11-23 | Gilead Sciences, Inc. | Oligonucleotide analogs with novel linkages |
US5264564A (en) | 1989-10-24 | 1993-11-23 | Gilead Sciences | Oligonucleotide analogs with novel linkages |
US5670633A (en) | 1990-01-11 | 1997-09-23 | Isis Pharmaceuticals, Inc. | Sugar modified oligonucleotides that detect and modulate gene expression |
US6005087A (en) | 1995-06-06 | 1999-12-21 | Isis Pharmaceuticals, Inc. | 2'-modified oligonucleotides |
US6153737A (en) | 1990-01-11 | 2000-11-28 | Isis Pharmaceuticals, Inc. | Derivatized oligonucleotides having improved uptake and other properties |
US5214136A (en) | 1990-02-20 | 1993-05-25 | Gilead Sciences, Inc. | Anthraquinone-derivatives oligonucleotides |
US5962219A (en) | 1990-06-11 | 1999-10-05 | Nexstar Pharmaceuticals, Inc. | Systematic evolution of ligands by exponential enrichment: chemi-selex |
US5138045A (en) | 1990-07-27 | 1992-08-11 | Isis Pharmaceuticals | Polyamine conjugated oligonucleotides |
JP3257675B2 (ja) | 1990-10-12 | 2002-02-18 | マックス−プランク−ゲゼルシャフト ツール フェルデルング デル ビッセンシャフテン エー.ファウ. | 修飾リボザイム |
DE4216134A1 (de) | 1991-06-20 | 1992-12-24 | Europ Lab Molekularbiolog | Synthetische katalytische oligonukleotidstrukturen |
US6335434B1 (en) | 1998-06-16 | 2002-01-01 | Isis Pharmaceuticals, Inc., | Nucleosidic and non-nucleosidic folate conjugates |
US5652094A (en) | 1992-01-31 | 1997-07-29 | University Of Montreal | Nucleozymes |
US6469158B1 (en) | 1992-05-14 | 2002-10-22 | Ribozyme Pharmaceuticals, Incorporated | Synthesis, deprotection, analysis and purification of RNA and ribozymes |
WO1993023569A1 (en) | 1992-05-11 | 1993-11-25 | Ribozyme Pharmaceuticals, Inc. | Method and reagent for inhibiting viral replication |
US5977343A (en) | 1992-05-14 | 1999-11-02 | Ribozyme Pharmaceuticals, Inc. | Synthesis, deprotection, analysis and purification of RNA and ribozymes |
US5804683A (en) | 1992-05-14 | 1998-09-08 | Ribozyme Pharmaceuticals, Inc. | Deprotection of RNA with alkylamine |
ATE171210T1 (de) | 1992-07-02 | 1998-10-15 | Hybridon Inc | Selbststabilisierte oligonukleotide als therapeutika |
WO1994002595A1 (en) | 1992-07-17 | 1994-02-03 | Ribozyme Pharmaceuticals, Inc. | Method and reagent for treatment of animal diseases |
US6174868B1 (en) | 1992-09-10 | 2001-01-16 | Isis Pharmaceuticals, Inc. | Compositions and methods for treatment of hepatitis C virus-associated diseases |
US6235886B1 (en) | 1993-09-03 | 2001-05-22 | Isis Pharmaceuticals, Inc. | Methods of synthesis and use |
US5767264A (en) | 1993-01-22 | 1998-06-16 | Mta Zozponti Kemiai Kutato Intezet | Oligodeoxynucleotides containing 5-alkyl, 5-(1-alkenyl)- and 5-(1-alkynl) pyrimidines |
AU5961994A (en) | 1993-01-22 | 1994-08-15 | University Research Corporation | Localization of therapeutic agents |
US6410322B1 (en) | 1993-07-27 | 2002-06-25 | Hybridon Inc | Antisense oligonucleotide inhibition of vascular endothelial growth factor expression |
ATE227342T1 (de) | 1993-09-02 | 2002-11-15 | Ribozyme Pharm Inc | Enzymatische nukleiksaüre die nicht-nukleotide enthaltet |
ATE247128T1 (de) | 1993-09-03 | 2003-08-15 | Isis Pharmaceuticals Inc | Aminoderivatisierte nukleoside und oligonukleoside |
US5624803A (en) | 1993-10-14 | 1997-04-29 | The Regents Of The University Of California | In vivo oligonucleotide generator, and methods of testing the binding affinity of triplex forming oligonucleotides derived therefrom |
US5861288A (en) | 1993-10-18 | 1999-01-19 | Ribozyme Pharmaceuticals, Inc. | Catalytic DNA |
DK0725788T3 (da) | 1993-10-27 | 1999-08-23 | Ribozyme Pharm Inc | 2'-amido- og 2'-peptidomodificerede oligonukleotider |
DE4338704A1 (de) | 1993-11-12 | 1995-05-18 | Hoechst Ag | Stabilisierte Oligonucleotide und deren Verwendung |
US5587471A (en) | 1994-01-11 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Method of making oligonucleotide libraries |
US5902880A (en) | 1994-08-19 | 1999-05-11 | Ribozyme Pharmaceuticals, Inc. | RNA polymerase III-based expression of therapeutic RNAs |
US5627053A (en) | 1994-03-29 | 1997-05-06 | Ribozyme Pharmaceuticals, Inc. | 2'deoxy-2'-alkylnucleotide containing nucleic acid |
US6447796B1 (en) | 1994-05-16 | 2002-09-10 | The United States Of America As Represented By The Secretary Of The Army | Sustained release hydrophobic bioactive PLGA microspheres |
US6146886A (en) | 1994-08-19 | 2000-11-14 | Ribozyme Pharmaceuticals, Inc. | RNA polymerase III-based expression of therapeutic RNAs |
US5820873A (en) | 1994-09-30 | 1998-10-13 | The University Of British Columbia | Polyethylene glycol modified ceramide lipids and liposome uses thereof |
US5753613A (en) | 1994-09-30 | 1998-05-19 | Inex Pharmaceuticals Corporation | Compositions for the introduction of polyanionic materials into cells |
US5885613A (en) | 1994-09-30 | 1999-03-23 | The University Of British Columbia | Bilayer stabilizing components and their use in forming programmable fusogenic liposomes |
AU4412096A (en) | 1994-12-13 | 1996-07-03 | Ribozyme Pharmaceuticals, Inc. | Method and reagent for treatment of arthritic conditions, induction of graft tolerance and reversal of immune responses |
US5716824A (en) | 1995-04-20 | 1998-02-10 | Ribozyme Pharmaceuticals, Inc. | 2'-O-alkylthioalkyl and 2-C-alkylthioalkyl-containing enzymatic nucleic acids (ribozymes) |
US5705385A (en) | 1995-06-07 | 1998-01-06 | Inex Pharmaceuticals Corporation | Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer |
IL122290A0 (en) | 1995-06-07 | 1998-04-05 | Inex Pharmaceuticals Corp | Lipid-nucleic acid complex its preparation and use |
US5981501A (en) | 1995-06-07 | 1999-11-09 | Inex Pharmaceuticals Corp. | Methods for encapsulating plasmids in lipid bilayers |
US7422902B1 (en) | 1995-06-07 | 2008-09-09 | The University Of British Columbia | Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer |
US5968909A (en) | 1995-08-04 | 1999-10-19 | Hybridon, Inc. | Method of modulating gene expression with reduced immunostimulatory response |
CN1120707C (zh) | 1995-11-22 | 2003-09-10 | 约翰斯·霍普金斯大学 | 增强生物分子的细胞摄取的配体 |
US5998203A (en) | 1996-04-16 | 1999-12-07 | Ribozyme Pharmaceuticals, Inc. | Enzymatic nucleic acids containing 5'-and/or 3'-cap structures |
CA2253382A1 (en) | 1996-01-16 | 1997-07-24 | Ribozyme Pharmaceuticals, Inc. | Synthesis of methoxy nucleosides and enzymatic nucleic acid molecules |
US5898031A (en) | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
US5849902A (en) | 1996-09-26 | 1998-12-15 | Oligos Etc. Inc. | Three component chimeric antisense oligonucleotides |
US6248878B1 (en) | 1996-12-24 | 2001-06-19 | Ribozyme Pharmaceuticals, Inc. | Nucleoside analogs |
CA2275964A1 (en) | 1996-12-24 | 1998-07-02 | Ribozyme Pharmaceuticals, Inc. | Synthesis of nucleosides and polynucleotides |
US6001311A (en) | 1997-02-05 | 1999-12-14 | Protogene Laboratories, Inc. | Apparatus for diverse chemical synthesis using two-dimensional array |
US6235310B1 (en) | 1997-04-04 | 2001-05-22 | Valentis, Inc. | Methods of delivery using cationic lipids and helper lipids |
DE69841002D1 (de) | 1997-05-14 | 2009-09-03 | Univ British Columbia | Hochwirksame verkapselung von nukleinsäuren in lipidvesikeln |
US6835395B1 (en) | 1997-05-14 | 2004-12-28 | The University Of British Columbia | Composition containing small multilamellar oligodeoxynucleotide-containing lipid vesicles |
ATE255882T1 (de) | 1997-06-23 | 2003-12-15 | Sequus Pharm Inc | Liposomen-umschlossene polynukleotidzusammensetzung sowie verfahren |
US6395713B1 (en) | 1997-07-23 | 2002-05-28 | Ribozyme Pharmaceuticals, Inc. | Compositions for the delivery of negatively charged molecules |
TW589189B (en) | 1997-08-04 | 2004-06-01 | Scras | Kit containing at least one double-stranded RNA combined with at least one anti-viral agent for therapeutic use in the treatment of a viral disease, notably of viral hepatitis |
CN1273476C (zh) | 1997-09-12 | 2006-09-06 | 埃克西康有限公司 | 寡核苷酸类似物 |
WO1999031262A2 (en) | 1997-12-16 | 1999-06-24 | Valentis, Inc. | Needle-free injection of formulated nucleic acid molecules |
US6506559B1 (en) | 1997-12-23 | 2003-01-14 | Carnegie Institute Of Washington | Genetic inhibition by double-stranded RNA |
US6835393B2 (en) | 1998-01-05 | 2004-12-28 | University Of Washington | Enhanced transport using membrane disruptive agents |
US6410328B1 (en) | 1998-02-03 | 2002-06-25 | Protiva Biotherapeutics Inc. | Sensitizing cells to compounds using lipid-mediated gene and compound delivery |
JP2003525017A (ja) | 1998-04-20 | 2003-08-26 | リボザイム・ファーマシューティカルズ・インコーポレーテッド | 遺伝子発現を調節しうる新規な化学組成を有する核酸分子 |
AU751480B2 (en) | 1998-04-29 | 2002-08-15 | Ribozyme Pharmaceuticals, Inc. | Nucleoside triphosphates and their incorporation into ribozymes |
GB9827152D0 (en) | 1998-07-03 | 1999-02-03 | Devgen Nv | Characterisation of gene function using double stranded rna inhibition |
CA2335393C (en) | 1998-07-20 | 2008-09-23 | Inex Pharmaceuticals Corporation | Liposomal encapsulated nucleic acid-complexes |
AU3096800A (en) | 1998-10-26 | 2000-05-15 | Intervu, Inc. | Audience management for interactive network events |
EP2314700A1 (en) | 1999-01-28 | 2011-04-27 | Medical College of Georgia Research Institute, Inc | Composition and method for in vivo and in vitro attenuation of gene expression using double stranded RNA |
DE19956568A1 (de) | 1999-01-30 | 2000-08-17 | Roland Kreutzer | Verfahren und Medikament zur Hemmung der Expression eines vorgegebenen Gens |
WO2000053722A2 (en) | 1999-03-10 | 2000-09-14 | Phogen Limited | Delivery of nucleic acids and proteins to cells |
JP2002540118A (ja) | 1999-03-18 | 2002-11-26 | エクシコン エ/エス | キシロ−lna類似体 |
DE60029314T2 (de) | 1999-03-24 | 2007-07-12 | Exiqon A/S | Verbesserte Synthese für -2.2.1. I Bicyclo-Nukleoside |
NZ514348A (en) | 1999-05-04 | 2004-05-28 | Exiqon As | L-ribo-LNA analogues |
US8137695B2 (en) | 2006-08-18 | 2012-03-20 | Arrowhead Madison Inc. | Polyconjugates for in vivo delivery of polynucleotides |
MXPA02000402A (es) | 1999-07-14 | 2002-07-30 | Alza Corp | Lipopolimeros neutros y composiciones liposomales que contienen los mismos. |
CA2403243A1 (en) | 1999-08-31 | 2001-03-08 | Ribozyme Pharmaceuticals, Inc. | Nucleic acid based modulators of gene expression |
IL148916A0 (en) | 1999-10-04 | 2002-09-12 | Exiqon As | Design of high affinity rnase h recruiting oligonucleotide |
EP1235842A4 (en) | 1999-10-15 | 2003-04-23 | Univ Massachusetts | GENESIS OF THE RNA INTERFERENCE PATH AS AID OF TARGETED GENTIAN INTERFERENCE |
GB9927444D0 (en) | 1999-11-19 | 2000-01-19 | Cancer Res Campaign Tech | Inhibiting gene expression |
DE10160151A1 (de) | 2001-01-09 | 2003-06-26 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines vorgegebenen Zielgens |
DE10100586C1 (de) | 2001-01-09 | 2002-04-11 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines Ziegens |
US6602857B1 (en) | 2000-01-18 | 2003-08-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of PTP1B expression |
US6261840B1 (en) | 2000-01-18 | 2001-07-17 | Isis Pharmaceuticals, Inc. | Antisense modulation of PTP1B expression |
WO2003070918A2 (en) | 2002-02-20 | 2003-08-28 | Ribozyme Pharmaceuticals, Incorporated | Rna interference by modified short interfering nucleic acid |
US8273866B2 (en) | 2002-02-20 | 2012-09-25 | Merck Sharp & Dohme Corp. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (SINA) |
US7833992B2 (en) | 2001-05-18 | 2010-11-16 | Merck Sharpe & Dohme | Conjugates and compositions for cellular delivery |
US6401406B1 (en) | 2000-02-11 | 2002-06-11 | Domald K. Komara | Retainment device for concrete block inspection plates |
WO2002081628A2 (en) | 2001-04-05 | 2002-10-17 | Ribozyme Pharmaceuticals, Incorporated | Modulation of gene expression associated with inflammation proliferation and neurite outgrowth, using nucleic acid based technologies |
US8202979B2 (en) | 2002-02-20 | 2012-06-19 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid |
US7491805B2 (en) | 2001-05-18 | 2009-02-17 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
IL151928A0 (en) | 2000-03-30 | 2003-04-10 | Whitehead Biomedical Inst | Rna sequence-specific mediators of rna interference |
US20030190635A1 (en) | 2002-02-20 | 2003-10-09 | Mcswiggen James A. | RNA interference mediated treatment of Alzheimer's disease using short interfering RNA |
US6613567B1 (en) | 2000-09-15 | 2003-09-02 | Isis Pharmaceuticals, Inc. | Antisense inhibition of Her-2 expression |
DE60119562T2 (de) | 2000-10-04 | 2007-05-10 | Santaris Pharma A/S | Verbesserte synthese von purin-blockierten nukleinsäure-analoga |
US6998115B2 (en) | 2000-10-10 | 2006-02-14 | Massachusetts Institute Of Technology | Biodegradable poly(β-amino esters) and uses thereof |
US7427394B2 (en) | 2000-10-10 | 2008-09-23 | Massachusetts Institute Of Technology | Biodegradable poly(β-amino esters) and uses thereof |
WO2002043771A2 (en) | 2000-12-01 | 2002-06-06 | Cell Works Inc. | Conjugates of glycosylated/galactosylated peptide |
JP4095895B2 (ja) | 2000-12-01 | 2008-06-04 | マックス−プランク−ゲゼルシャフト ツール フォーデルング デル ヴィッセンシャフテン エー.ヴェー. | Rna干渉を媒介する短鎖rna分子 |
US20020130430A1 (en) | 2000-12-29 | 2002-09-19 | Castor Trevor Percival | Methods for making polymer microspheres/nanospheres and encapsulating therapeutic proteins and other products |
WO2004028341A2 (en) | 2001-03-19 | 2004-04-08 | Decode Genetics Ehf. | Susceptibility gene for human stroke; methods of treatment |
US20050164220A1 (en) | 2001-03-19 | 2005-07-28 | Decode Genetics Ehf. | Susceptibility gene for human stroke: method of treatment |
CA2442092A1 (en) | 2001-03-26 | 2002-10-17 | Ribozyme Pharmaceuticals, Inc. | Oligonucleotide mediated inhibition of hepatitis b virus and hepatitis c virus replication |
WO2002087541A1 (en) | 2001-04-30 | 2002-11-07 | Protiva Biotherapeutics Inc. | Lipid-based formulations for gene transfer |
EP1572067A4 (en) | 2001-05-18 | 2009-05-13 | Sirna Therapeutics Inc | CONJUGATES AND COMPOSITIONS FOR CELL DELIVERY |
WO2003070910A2 (en) | 2002-02-20 | 2003-08-28 | Ribozyme Pharmaceuticals, Incorporated | INHIBITION OF VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AND VEGF RECEPTOR GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
WO2003070197A2 (en) | 2002-02-20 | 2003-08-28 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF TGF-BETA AND TGF-BETA RECEPTOR GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
WO2003070972A2 (en) | 2002-02-20 | 2003-08-28 | Sirna Therapeutics Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF CHROMOSOME TRANSLOCATION GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
US20050148530A1 (en) | 2002-02-20 | 2005-07-07 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20040019001A1 (en) | 2002-02-20 | 2004-01-29 | Mcswiggen James A. | RNA interference mediated inhibition of protein typrosine phosphatase-1B (PTP-1B) gene expression using short interfering RNA |
WO2003070897A2 (en) | 2002-02-20 | 2003-08-28 | Ribozyme Pharmaceuticals, Incorporated | RNA INTERFERENCE MEDIATED INHIBITION OF TNF AND TNF RECEPTOR SUPERFAMILY GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
WO2003070887A2 (en) | 2002-02-20 | 2003-08-28 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF POLYCOMB GROUP PROTEIN EZH2 GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
US20030130186A1 (en) | 2001-07-20 | 2003-07-10 | Chandra Vargeese | Conjugates and compositions for cellular delivery |
US20030175950A1 (en) | 2001-05-29 | 2003-09-18 | Mcswiggen James A. | RNA interference mediated inhibition of HIV gene expression using short interfering RNA |
US20030125241A1 (en) | 2001-05-18 | 2003-07-03 | Margit Wissenbach | Therapeutic uses of LNA-modified oligonucleotides in infectious diseases |
WO2003072590A1 (en) | 2002-02-20 | 2003-09-04 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of map kinase genes |
EP1627061B1 (en) | 2001-05-18 | 2009-08-12 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING CHEMICALLY MODIFIED SHORT INTERFERING NUCLEIC ACID (siNA) |
WO2003070912A2 (en) | 2001-06-06 | 2003-08-28 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF EPIDERMAL GROWTH FACTOR RECEPTOR GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
WO2004097020A2 (en) | 2003-04-25 | 2004-11-11 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of map kinase gene expression |
US20050196781A1 (en) | 2001-05-18 | 2005-09-08 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of STAT3 gene expression using short interfering nucleic acid (siNA) |
WO2003070884A2 (en) | 2002-02-20 | 2003-08-28 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF MDR P-GLYCOPROTEIN GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
US7109165B2 (en) | 2001-05-18 | 2006-09-19 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
JP2005500025A (ja) | 2001-05-29 | 2005-01-06 | サーナ・セラピューティクス・インコーポレイテッド | 女性生殖疾病及び状態の核酸に基づく調節 |
WO2003006475A2 (en) | 2001-07-12 | 2003-01-23 | Santaris Pharma A/S | Method for preparation of lna phosphoramidites |
AU2002312543A1 (en) | 2001-08-01 | 2003-02-17 | University Of Utah, Technology Transfer Office | Isoform-selective inhibitors and activators of pde3 cyclic |
US20050191627A1 (en) | 2001-09-28 | 2005-09-01 | Incyte Corporation | Enzymes |
CA2465129A1 (en) * | 2001-10-29 | 2003-05-08 | Mcgill University | Acyclic linker-containing oligonucleotides and uses thereof |
US7060498B1 (en) | 2001-11-28 | 2006-06-13 | Genta Salus Llc | Polycationic water soluble copolymer and method for transferring polyanionic macromolecules across biological barriers |
US7141540B2 (en) | 2001-11-30 | 2006-11-28 | Genta Salus Llc | Cyclodextrin grafted biocompatible amphilphilic polymer and methods of preparation and use thereof |
AU2002357860A1 (en) | 2001-12-14 | 2003-06-30 | Incyte Genomics, Inc. | Enzymes |
EP1474433A4 (en) | 2002-02-20 | 2005-02-23 | Sirna Therapeutics Inc | TARGET LOCALIZATION TARGETED BY RNA INTERFERENCE AND TARGET VALIDATION WITH SHORT INTERFERING NUCLEIC ACID (siNA) |
AU2003210895A1 (en) | 2002-02-20 | 2003-09-09 | Ribozyme Pharmaceuticals, Inc. | Rna interference mediated inhibition of cyclin d1 gene expression using short interfering nucleic acid (sina) |
AU2003215161A1 (en) | 2002-02-20 | 2003-09-09 | Ribozyme Pharmaceuticals, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF TELOMERASE GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
EP1430157B1 (en) | 2002-02-20 | 2011-08-10 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF HEPATITIS C VIRUS (HCV) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
EP1465910A4 (en) | 2002-02-20 | 2005-03-16 | Sirna Therapeutics Inc | INHIBITION OF EXPRESSION OF RNA I-MEDIATED GENE CHECKPOINT KINASE-1 (CHK-1) USING NEAR-INTERFERENCE NUCLEIC ACID |
AU2003207708A1 (en) | 2002-02-20 | 2003-09-09 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of map kinase genes |
EP1463842A4 (en) | 2002-02-20 | 2006-01-25 | Sirna Therapeutics Inc | RNA-Interferent-mediated inhibition of protein gene expression for C-ALPHA (PKC-ALPHA) gene using SINA (Short Interfering Nucleic Acid) |
US7935812B2 (en) | 2002-02-20 | 2011-05-03 | Merck Sharp & Dohme Corp. | RNA interference mediated inhibition of hepatitis C virus (HCV) expression using short interfering nucleic acid (siNA) |
WO2003106476A1 (en) | 2002-02-20 | 2003-12-24 | Sirna Therapeutics, Inc | Nucleic acid mediated inhibition of enterococcus infection and cytolysin toxin activity |
AU2003219781A1 (en) | 2002-02-20 | 2003-09-09 | Sirna Therapeutics, Inc | RNA INTERFERENCE MEDIATED INHIBITION OF PROLIFERATING CELL NUCLEAR ANTIGEN (PCNA) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
US8232383B2 (en) | 2002-02-20 | 2012-07-31 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
EP1442143A4 (en) | 2002-02-20 | 2005-02-16 | Sirna Therapeutics Inc | INHIBITION OF RNA INTERFERENCE-INDUCED BCL2 GENE EXPRESSION USING SMALL INTERFERING NUCLEIC ACIDS (SINA) |
AU2003213203A1 (en) | 2002-02-20 | 2003-09-09 | Ribozyme Pharmaceuticals, Incorporated | Rna interference mediated inhibition of myc and myb genes or genes of their respective pathways |
EP1495041A4 (en) | 2002-02-20 | 2006-02-01 | Sirna Therapeutics Inc | RNA interferon-mediated inhibition of gene expression of G72 and D-amino acid oxidase (DAAO) using short-term interfering nucleic acid (siNA) |
NZ546806A (en) | 2002-03-27 | 2007-03-30 | Aegera Therapeutics Inc | Antisense IAP nucleobase oligomers and uses thereof |
US8101348B2 (en) * | 2002-07-10 | 2012-01-24 | Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. | RNA-interference by single-stranded RNA molecules |
EP2258847B2 (en) | 2002-08-05 | 2020-07-01 | Silence Therapeutics GmbH | Futher novel forms of interfering RNA molecules |
US20040029275A1 (en) * | 2002-08-10 | 2004-02-12 | David Brown | Methods and compositions for reducing target gene expression using cocktails of siRNAs or constructs expressing siRNAs |
US7923547B2 (en) | 2002-09-05 | 2011-04-12 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US8133903B2 (en) | 2003-10-21 | 2012-03-13 | Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center | Methods of use of inhibitors of phosphodiesterases and modulators of nitric oxide, reactive oxygen species, and metalloproteinases in the treatment of peyronie's disease, arteriosclerosis and other fibrotic diseases |
WO2004043978A2 (en) | 2002-11-05 | 2004-05-27 | Isis Pharmaceuticals, Inc. | 2'-methoxy substituted oligomeric compounds and compositions for use in gene modulations |
US7816337B2 (en) | 2003-02-18 | 2010-10-19 | Roche Madison Inc. | Reversible attachment of a membrane active polymer to a polynucleotide |
US6977223B2 (en) | 2003-03-07 | 2005-12-20 | Massachusetts Institute Of Technology | Three dimensional microfabrication |
EP1608733B1 (en) | 2003-04-02 | 2011-12-07 | Dharmacon, Inc. | Modified polynucleotides for use in rna interference |
EP1622572B1 (en) | 2003-04-30 | 2017-12-20 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
AU2005212433B2 (en) | 2003-05-23 | 2010-12-16 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using multifunctional short interfering nucleic acid (multifunctional sINA) |
EP2567693B1 (en) | 2003-07-16 | 2015-10-21 | Protiva Biotherapeutics Inc. | Lipid encapsulated interfering RNA |
NZ592917A (en) | 2003-09-15 | 2012-12-21 | Protiva Biotherapeutics Inc | Stable polyethyleneglycol (PEG) dialkyloxypropyl (DAA) lipid conjugates |
EP1670915A2 (en) | 2003-09-16 | 2006-06-21 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF HEPATITIS C VIRUS (HCV) EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
US7425544B2 (en) * | 2003-09-18 | 2008-09-16 | Eli Lilly And Company | Modulation of eIF4E expression |
US7943179B2 (en) | 2003-09-23 | 2011-05-17 | Massachusetts Institute Of Technology | pH triggerable polymeric particles |
BRPI0414886A (pt) | 2003-09-29 | 2006-12-12 | Topigen Pharma Inc | composições de oligonucleotìdeo e métodos para o tratamento de doença incluindo condições inflamatórias |
EP1675948A2 (en) | 2003-10-23 | 2006-07-05 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED TREATMENT OF PARKINSON DISEASE USING SHORT INTERERING NUCLEIC ACID (siNA) |
WO2005045035A2 (en) | 2003-10-23 | 2005-05-19 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF NOGO AND NOGO RECEPTOR GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
EP1709195B1 (en) | 2003-12-19 | 2014-01-22 | Novartis Vaccines and Diagnostics, Inc. | Cell transfecting formulations of small interfering rna, related compositions and methods of making and use |
EP2700720A3 (en) | 2004-03-15 | 2015-01-28 | Isis Pharmaceuticals, Inc. | Compositions and methods for optimizing cleavage of RNA by RNASE H |
CA2564616C (en) | 2004-04-20 | 2016-08-30 | Nastech Pharmaceutical Company Inc. | Methods and compositions for enhancing delivery of double-stranded rna or a double-stranded hybrid nucleic acid to regulate gene expression in mammalian cells |
US20060040882A1 (en) | 2004-05-04 | 2006-02-23 | Lishan Chen | Compostions and methods for enhancing delivery of nucleic acids into cells and for modifying expression of target genes in cells |
US7811602B2 (en) | 2004-05-17 | 2010-10-12 | Tekmira Pharmaceuticals Corporation | Liposomal formulations comprising dihydrosphingomyelin and methods of use thereof |
US20060019258A1 (en) | 2004-07-20 | 2006-01-26 | Illumina, Inc. | Methods and compositions for detection of small interfering RNA and micro-RNA |
US20060142228A1 (en) * | 2004-12-23 | 2006-06-29 | Ambion, Inc. | Methods and compositions concerning siRNA's as mediators of RNA interference |
CA2594334A1 (en) * | 2005-01-07 | 2006-07-13 | Alnylam Pharmaceuticals, Inc. | Rnai modulation of rsv and therapeutic uses thereof |
CA2597724A1 (en) | 2005-02-14 | 2007-08-02 | Sirna Therapeutics, Inc. | Cationic lipids and formulated molecular compositions containing them |
US7404969B2 (en) | 2005-02-14 | 2008-07-29 | Sirna Therapeutics, Inc. | Lipid nanoparticle based compositions and methods for the delivery of biologically active molecules |
US20070213292A1 (en) | 2005-08-10 | 2007-09-13 | The Rockefeller University | Chemically modified oligonucleotides for use in modulating micro RNA and uses thereof |
CA2619876A1 (en) | 2005-08-17 | 2007-02-22 | Sirna Therapeutics, Inc. | Chemically modified short interfering nucleic acid molecules that mediate rna interference |
US20090176725A1 (en) | 2005-08-17 | 2009-07-09 | Sirna Therapeutics Inc. | Chemically modified short interfering nucleic acid molecules that mediate rna interference |
EP2126141A4 (en) * | 2007-03-15 | 2010-08-11 | Univ Cleveland Hospitals | SCREENING, DIAGNOSIS, TREATMENT AND PROGNOSIS OF PATHOPHYSIOLOGIC CONDITIONS BY RNA REGULATION |
MX2009012568A (es) | 2007-05-22 | 2009-12-08 | Mdrna Inc | Oligonucleotidos de acido ribonucleico sustituidos con hidroximetilo y complejos de acido ribonucleico. |
US8691965B2 (en) * | 2007-06-14 | 2014-04-08 | Mirx Therapeutics Aps | Oligonucleotides for modulating target RNA activity |
BRPI0817605A2 (pt) * | 2007-10-03 | 2017-05-09 | Quark Pharmaceuticals Inc | novas estruturas de sirna |
WO2009082607A2 (en) | 2007-12-04 | 2009-07-02 | Alnylam Pharmaceuticals, Inc. | Targeting lipids |
EP2231194B1 (en) | 2007-12-04 | 2017-02-22 | Alnylam Pharmaceuticals Inc. | Folate-irna conjugates |
WO2010006237A2 (en) | 2008-07-11 | 2010-01-14 | Alnylam Pharmaceuticals, Inc. | Phosphorothioate oligonucleotides non-nucleosidic phosphorothiotes as delivery agents for irna agents |
WO2010028079A2 (en) * | 2008-09-02 | 2010-03-11 | Alnylam Pharmaceuticals, Inc | Synthetic methods and derivatives of triphosphate oligonucleotides |
EP2447274B1 (en) * | 2008-10-24 | 2017-10-04 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds and methods |
WO2010093705A2 (en) * | 2009-02-10 | 2010-08-19 | Idera Pharmaceuticals, Inc. | Synthetic rna-based agonists of tlr7 |
EP2669290A1 (en) * | 2009-03-02 | 2013-12-04 | Alnylam Pharmaceuticals Inc. | Nucleic Acid Chemical Modifications |
US9096850B2 (en) * | 2009-08-24 | 2015-08-04 | Sirna Therapeutics, Inc. | Segmented micro RNA mimetics |
ES2646097T3 (es) * | 2009-08-27 | 2017-12-12 | Idera Pharmaceuticals, Inc. | Composición para inhibir la expresión de genes y sus usos |
WO2011133876A2 (en) | 2010-04-22 | 2011-10-27 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising acyclic and abasic nucleosides and analogs |
EP3372684B1 (en) * | 2010-08-24 | 2020-10-07 | Sirna Therapeutics, Inc. | Single-stranded rnai agents containing an internal, non-nucleic acid spacer |
EP2640400A4 (en) | 2010-11-19 | 2016-01-20 | Sirna Therapeutics Inc | POLYMERIC POLYMERS (AMIDE) FOR THE ADMINISTRATION OF OLIGONUCLEOTIDES |
EA201490993A1 (ru) | 2011-11-18 | 2014-09-30 | Элнилэм Фармасьютикалз, Инк. | МОДИФИЦИРОВАННЫЕ СРЕДСТВА РНКи |
US20150299696A1 (en) | 2012-05-02 | 2015-10-22 | Sirna Therapeutics, Inc. | SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS |
-
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- 2011-08-19 EP EP18000072.1A patent/EP3372684B1/en active Active
- 2011-08-19 CN CN2011800473832A patent/CN103140582A/zh active Pending
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- 2011-08-19 US US13/818,306 patent/US9243246B2/en active Active
- 2011-08-19 EP EP11820420.5A patent/EP2609198B8/en active Active
- 2011-08-19 WO PCT/US2011/048338 patent/WO2012027206A1/en active Application Filing
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-
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-
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-
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- 2023-05-02 JP JP2023076252A patent/JP2023100832A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004014933A1 (en) * | 2002-08-07 | 2004-02-19 | University Of Massachusetts | Compositions for rna interference and methods of use thereof |
WO2006102970A2 (en) * | 2005-03-08 | 2006-10-05 | Qiagen Gmbh | Modified short interfering rna |
US20080311040A1 (en) * | 2007-03-06 | 2008-12-18 | Flagship Ventures | METHODS AND COMPOSITIONS FOR IMPROVED THERAPEUTIC EFFECTS WITH siRNA |
Non-Patent Citations (3)
Title |
---|
JPN6015035010; Bioorg. Med. Chem. Lett. Vol.19, No.3, 2009, pp.875-877 * |
JPN7015002420; Nucleic Acids Symp. Ser. No.53, 2009, pp.119-120 * |
JPN7015002422; Nucleic Acids Research Vol.34, No.9, 2006, pp.2773-2781 * |
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JP2019030312A (ja) * | 2013-12-17 | 2019-02-28 | インコドゥヂュン シーオー.,エルティーディー | オフターゲットを防ぐために変形したrna干渉を誘導する核酸、遺伝子発現抑制用組成物、遺伝子発現抑制用キット、細胞内ターゲット遺伝子の発現抑制方法、オフターゲット効果を抑制する方法 |
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EP2609198B1 (en) | 2018-02-21 |
EP2609198B8 (en) | 2018-03-28 |
EP2609198A1 (en) | 2013-07-03 |
US9845466B2 (en) | 2017-12-19 |
US20130171242A1 (en) | 2013-07-04 |
JP2017079776A (ja) | 2017-05-18 |
EP3372684B1 (en) | 2020-10-07 |
CN103140582A (zh) | 2013-06-05 |
JP6106085B2 (ja) | 2017-03-29 |
WO2012027206A1 (en) | 2012-03-01 |
US20160222381A1 (en) | 2016-08-04 |
US10584335B2 (en) | 2020-03-10 |
JP2022037070A (ja) | 2022-03-08 |
EP2609198A4 (en) | 2014-11-19 |
KR20130137160A (ko) | 2013-12-16 |
EP3372684A1 (en) | 2018-09-12 |
US20180080024A1 (en) | 2018-03-22 |
JP2023100832A (ja) | 2023-07-19 |
JP2020074788A (ja) | 2020-05-21 |
US9243246B2 (en) | 2016-01-26 |
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