JP3940407B2 - 非ヌクレオチドを含有する酵素性核酸 - Google Patents
非ヌクレオチドを含有する酵素性核酸 Download PDFInfo
- Publication number
- JP3940407B2 JP3940407B2 JP2004121910A JP2004121910A JP3940407B2 JP 3940407 B2 JP3940407 B2 JP 3940407B2 JP 2004121910 A JP2004121910 A JP 2004121910A JP 2004121910 A JP2004121910 A JP 2004121910A JP 3940407 B2 JP3940407 B2 JP 3940407B2
- Authority
- JP
- Japan
- Prior art keywords
- rna
- nucleic acid
- nucleotide
- ribozyme
- ribozymes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/111—General methods applicable to biologically active non-coding nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/24—Metalloendopeptidases (3.4.24)
- C12Y304/24017—Stromelysin 1 (3.4.24.17)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/12—Type of nucleic acid catalytic nucleic acids, e.g. ribozymes
- C12N2310/121—Hammerhead
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/318—Chemical structure of the backbone where the PO2 is completely replaced, e.g. MMI or formacetal
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/321—2'-O-R Modification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/322—2'-R Modification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/33—Chemical structure of the base
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/33—Chemical structure of the base
- C12N2310/332—Abasic residue
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/346—Spatial arrangement of the modifications having a combination of backbone and sugar modifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2330/00—Production
- C12N2330/30—Production chemically synthesised
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Biophysics (AREA)
- Virology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Description
(表1)
リボザイムの性質
グループI イントロン
大きさ:〜300から>1000ヌクレオチド
切断部位の5’につながる標的配列においてUが必要である。
切断部位の5’側において4〜6ヌクレオチドが結合する
このクラスにおいて100を越える公知のヌクレオチドが、テトラヒメナ・サーモフィラのrRNA、黴ミトコンドリア、クロロプラオスト、ファージT4、ブルー・グリーンアルガエおよび他のものから単離されている。
RNアーゼP RNA(M1 RNA)
大きさ:〜290から400ヌクレオチド
リボヌクレオチド酵素のRNA部分。tRNAプレカーサーを切断して成熟tRNAを作製する。このグループはおよそ10個公知のものがあるが、すべては細菌由来である。
ハンマーヘッドリボザイム
大きさ:〜13から40ヌクレオチド
切断部位の5’に直接ついているUH標的配列が必要である
さまざまな数のヌクレオチドが切断部位の両側へ結合する。
このクラスには14個の公知のものがある。RNAを感染剤として用いる植物病原(ウイルソイズ)に認められる(図1)。
ヘアピンリボザイム
大きさ:〜50ヌクレオチド
切断部位の3’に直接ついているGUC配列が必要である。
切断部位の5’側に4ヌクレオチドが結合し、様々な数のヌクレオチドが切断部位の3’側に結合している。
このクラスには1個のみの公知のヌクレオチドがある。これはRNAを感染用に用いる植物病原(タバコリングスポットウイルスのサテライトRNA)から得られたものである(図2)。
肝炎デルタウイルス(HDV)リボザイム
大きさ:〜60ヌクレオチド(現在)
標的RNAを切断することが近年証明された。
必要とする配列は完全には解明されていない。
結合部位と構造的な要求性に関しても完全には解明されていないが、切断部位の5’側にはいずれの配列も必要とはされない。
このクラスには1個のみの公知のヌクレオチドがある。これはヒトのHDVから単離されたものである(図3)。
図1は当該技術分野で公知のハンマーヘッドリボザイム領域の線図である。
図2は当該技術分野で公知のヘアピンリボザイム領域の一般構造の線図である。
図3は当該技術分野で公知の肝炎デルタウイルスリボザイム領域の一般構造の線図である。
図4は核酸酵素に組込むことができる各種の非ヌクレオチド擬似体(ミメティック)の線図である。図4では標準的な略語を用いている。化合物1において、Xは各々、独立して、酸素、窒素、硫黄または置換炭素を含有するアルキル、アルケンまたは炭素原子1〜10個の長さの均等な連鎖である。化合物6、6a、7、8、9および10において、Yは各々、独立して、核酸酵素の他の部分に対するホスホジエステル、エーテルまたはアミド結合部分である。化合物4と5において、Rは各々、独立してH、OH、保護されたOH、0−アルキル、アルケニルもしくはアルキニル、または炭素原子が1〜10個のアルキル、アルケニルもしくはアルキニルである。
図5は各種の非ヌクレオチド擬似体(ミメティック)と核酸酵素に組込むのに好ましい位置を示す線図である。具体的に述べると、擬似体1〜10は、ステムIIの二つのストランドを接続するループ(図5中に/ /で示す)を置換することができる。ステムII自体は1〜10個の塩基対である。後記の実施例1と2では、化合物1と2が、長さが1〜5個の塩基対のステムIIを有する分子中に組込まれた。また化合物1、4および5は、ステムIとIIIの認識アームの中のヌクレオチド、またはステムII自体の中のヌクレオチドを置換する。
図6はペリレンベースの非ヌクレオチド擬似体のホスホルアミダイト3の合成を示す線図である。
図7は非塩基のデオキシリボースまたはリボースの非ヌクレオチド擬似体ホスホルアミダイトの合成を示す線図である。
図8aと8bはそれぞれ、8nMまたは40nMの各種リボザイムによる基質の切断を示す線図である。
本発明に有用な非ヌクレオチド擬似体としては先に一般的に述べたものがある。当該技術分野の当業者は、これらの擬似体は、標準の方法によって酵素分子中に所望の位置に組込むことができることが分かるであろう。標準の実験を行い例えば分子を合成してその酵素活性を試験することによってその最適位置を決定して、適切な選択を行うことができる。最適の分子は、酵素活性を得るのに必要な公知のリボヌクレオチドを含有し、かつ分子の構造を簡単なものに変える非ヌクレオチドを含有している。要求されることは、いくつかのヌクレオチドが一つの非ヌクレオチドで置換され、酵素分子合成の合成ステップが節約されて、RNAまたはDNAにさえ比べて酵素分子の安定性が高められることである。
ポリエステルスペーサーである化合物1(図4;X=0、n=2または4)の、n=2もしくは4のものを単独でまたはn=2のものを二重に、ハンマーヘッドリボザイムのステムIIのベースにループ2を置換して組込んだところ触媒効率が低いリボザイムが生成したことが分かった。利用した合成法は、Usmanら、J.Am.Chem.Soc.、109巻、7845頁、1987年;およびScaringeら、Nucleic Acids Res.、18巻、5433頁、1990年に記載されているような通常のRNA合成法の手順にしたがった合成法であり、通常の核酸保護基と核酸カップリング基が用いられ、例えば5'末端ではジメトキシトリチルが3'末端ではホスホルアミダイトが用いられる。段階的カップリングの平均収率は>98%であった。これらの型の擬似体の構造はまだ最適化されていないが、先に述べたように、このことは標準の試験法を用いて容易に達成することができるであろう。これらの試験は、このような擬似体が、触媒活性を維持しながらリボザイムのループと一部分を置換する可能性を示している。これらの擬似体はハンマーヘッドリボザイム中に組込むことができるだけでなく、ヘアピン、肝炎デルタウイルス、またはグループ1もしくはグループ2のイントロン中にも組込むことができる。したがってこれら擬似体は任意の核酸構造中に置換モチーフとして汎用することができる。このような擬似体を用いると、非ヌクレオチド擬似体なしのオリゴヌクレオチドを使用する場合と比べて、最終の核酸分子から約2〜10個のヌクレオチドを省略することができる。
別の実施例で、ハンマーヘッドリボザイムのステムIIC−Gのベースに対する特異的なリンカーを設計した。本発明の発明者は、C−Gの塩基対のC1'炭素間の距離は約16オングストロームであると考えている。これら二つのRNAピースを、共有結合類似体のC−G塩基対で結合するため、GとCそれぞれの残基の3'−OHと5'−OHの間にリンカーを含有する新しい型の二量体ホスホルアミダイトを構築することができる。図4に示す二つの型の塩基対擬似体2または3は剛性の芳香族スペーサーである。これらのスペーサーを、実施例1に記載されているようにして、ループ2を置換してハンマーヘッドリボザイムのステムIIのベースに組込んだところ、触媒効率が低いリボザイムが生成することが分かった。他の擬似体は、Nielsenら、Science、254巻、1497頁、1991年に記載されているポリアミド骨格に類似の可撓性のアルキルスペーサーである(図4の6またはその誘導体6a;Zuckermanら、J.Am.Chem.Soc.、114巻、10464頁、1992年参照)。このような擬似体を使用すると、非ヌクレオチド擬似体なしのオリゴヌクレオチドを使用する場合と比べて、最終の核酸分子から約2〜10個のヌクレオチドを省略することができる。
この化合物は、Salunkheら、J.Am.Chem.Soc.、114巻、6324頁、1992年に初めて報告された。その合成法は以下のように改変した。DMF(12ml)中のテレフタル酸(1.0g、6.0mmol)に、EDC(2.54g、13.2mmol)、アミノヘキサノール(1.55g、13.2mmol)およびN−メチルモルホリン(1.45ml、13.2mmol)を添加した。その反応混合物を一夜撹拌したがその時、溶液は濁っていた。その反応混合物に水を添加して生成物を沈澱させた。固形分をろ取して水で洗浄し乾燥して562mg(25.7%)のジオールを得た。
図6に示すように、キノリン(10ml)中の3、4、9、10−ペリレンテトラカルボン酸二無水物11(1.0g、2.55mmol)に、エタノールアミン(919μl、15.3mmol)とZnOAc・2.5H2O(140mg、0.638mmol)を添加した。反応混合物を190℃で8時間加熱した。得られた溶液を冷却し、1NHClを添加して生成物を沈澱させ、次いでその混合物をろ過した。固形分を、ろ液がもはや淡緑色でなくなるまで熱10%CaCO3溶液で洗浄した。残留した鮮やかな赤色の沈澱12を乾燥した。
化合物4(R=H)をIyerら、Nuleic Acids Res.、18巻、2855頁、1990年にしたがって製造した。図7に示すように、化合物4と5(R=o−t−ブチルジメチルシリル)のホスホルアミダイトを以下のようにして製造した。
図8aと8bを参照して、基質の切断を、8nMと40nMの濃度で各種修飾リボザイムを未修飾リボザイムと比較することによって示す。具体的に述べると、配列ucuccA UCU GAU GAG GCC GAA AGG CCG AAA Auc ccu(小文字は、2'−0−メチル基を含有する)の対照リボザイムを、リボザイムA(ucu ccA UCU GAU GAG GCC SGG CCG AAA Auc ccu)、B(ucu ccA UCU GAU GAG CSG CG AAA Auc ccu)、C(ucu ccA UCU GAU GAG GCC bbb bGG CCG AAA Auc ccu)、およびD(ucu ccA UCU GAU GAG Cbb bbG CGAA AAu ccc u)(S=ヘキサエチレングリコールリンカー;およびb=非塩基のヌクレオチド4)と比較した。これらはすべて、基質を切断する活性を有していた。
選択されたリボザイムは例えば、イオン導入法、電気穿孔法またはイオン対分子もしくは共有結合付加物、およびその外の薬理学的に承認された送達法を用いて、適切な送達ビヒクル例えばリポソーム、放出調節媒体により関連組織にリボザイムを外因的に送達することによって、ウイルス感染患者または疾病患者に予防的に投与することができる。投与経路としては、筋肉内、エアゾール、経口(錠剤または丸剤の形態)、局所、全身、眼、腹腔内および/またはくも膜下の経路がある。
a.リポソーム内への封入
b.レトロウイルスベクターによる形質導入
c.コレステロールとの接合
d.大部分のsnRNAまたは核タンパク質に見られる抗原結合部位または核標的部位を利用する核コンパートメントへの局在化
e.ヌクレオチド誘導体を用いることによるリボザイムの電荷の中和、および f.血液幹細胞を用いて行うリボザイムの全身体への分布、である。
静脈内に注射されたリポソームは、肝臓、肺および脾臓への蓄積を示す。その組成と大きさを調節して、注射投与量の30〜40%が蓄積されるようにすることができる。残りの投与量は血流中を24時間まで循環する。
その外の実施態様は後記の特許請求の範囲に含まれている。
Claims (4)
- 該核酸分子が、2’糖の修飾を有するヌクレオチドを少なくとも1つ含む、請求項1に記載の核酸分子。
- 該核酸分子が、ホスフェート骨格の修飾を有するヌクレオチドを少なくとも1つ含む、請求項1または2に記載の核酸分子。
- 該核酸分子が、5’キャップまたは3’キャップあるいは5’キャップと3’キャップの両方を含む、請求項1から3のいずれかに記載の核酸分子。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11617793A | 1993-09-02 | 1993-09-02 | |
US15248193A | 1993-11-12 | 1993-11-12 | |
US23374894A | 1994-04-19 | 1994-04-19 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP8508146A Division JPH10507105A (ja) | 1994-08-12 | 1995-08-11 | 内視鏡 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2004215675A JP2004215675A (ja) | 2004-08-05 |
JP2004215675A5 JP2004215675A5 (ja) | 2005-07-07 |
JP3940407B2 true JP3940407B2 (ja) | 2007-07-04 |
Family
ID=27381788
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP7508146A Pending JPH09502092A (ja) | 1993-09-02 | 1994-08-19 | 非ヌクレオチドを含有する酵素性核酸 |
JP2004121910A Expired - Fee Related JP3940407B2 (ja) | 1993-09-02 | 2004-04-16 | 非ヌクレオチドを含有する酵素性核酸 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP7508146A Pending JPH09502092A (ja) | 1993-09-02 | 1994-08-19 | 非ヌクレオチドを含有する酵素性核酸 |
Country Status (10)
Country | Link |
---|---|
US (5) | US5891683A (ja) |
EP (3) | EP0748382B1 (ja) |
JP (2) | JPH09502092A (ja) |
AT (1) | ATE227342T1 (ja) |
CA (1) | CA2169645A1 (ja) |
DE (1) | DE69431669T2 (ja) |
DK (1) | DK0748382T3 (ja) |
ES (1) | ES2186690T3 (ja) |
PT (1) | PT748382E (ja) |
WO (1) | WO1995006731A2 (ja) |
Families Citing this family (314)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6399754B1 (en) * | 1991-12-24 | 2002-06-04 | Isis Pharmaceuticals, Inc. | Sugar modified oligonucleotides |
EP0748382B1 (en) | 1993-09-02 | 2002-11-06 | Ribozyme Pharmaceuticals, Inc. | Non-nucleotide containing enzymatic nucleic acid |
AU687479B2 (en) | 1993-11-08 | 1998-02-26 | Ribozyme Pharmaceuticals, Inc. | Base-modified enzymatic nucleic acid |
US5672501A (en) * | 1994-12-23 | 1997-09-30 | Ribozyme Pharmaceuticals, Inc. | Base-modified enzymatic nucleic acid |
US7034009B2 (en) | 1995-10-26 | 2006-04-25 | Sirna Therapeutics, Inc. | Enzymatic nucleic acid-mediated treatment of ocular diseases or conditions related to levels of vascular endothelial growth factor receptor (VEGF-R) |
US5728818A (en) * | 1996-01-16 | 1998-03-17 | Ribozyme Pharmaceuticals, Inc. | Chemical linkage of ribozyme protions |
US5998203A (en) * | 1996-04-16 | 1999-12-07 | Ribozyme Pharmaceuticals, Inc. | Enzymatic nucleic acids containing 5'-and/or 3'-cap structures |
US20040203024A1 (en) * | 1996-06-06 | 2004-10-14 | Baker Brenda F. | Modified oligonucleotides for use in RNA interference |
US5898031A (en) * | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
US20040171028A1 (en) * | 1996-06-06 | 2004-09-02 | Baker Brenda F. | Phosphorous-linked oligomeric compounds and their use in gene modulation |
US20050053976A1 (en) * | 1996-06-06 | 2005-03-10 | Baker Brenda F. | Chimeric oligomeric compounds and their use in gene modulation |
US20040147022A1 (en) * | 1996-06-06 | 2004-07-29 | Baker Brenda F. | 2'-methoxy substituted oligomeric compounds and compositions for use in gene modulations |
US20040266706A1 (en) * | 2002-11-05 | 2004-12-30 | Muthiah Manoharan | Cross-linked oligomeric compounds and their use in gene modulation |
US20050119470A1 (en) * | 1996-06-06 | 2005-06-02 | Muthiah Manoharan | Conjugated oligomeric compounds and their use in gene modulation |
US20030044941A1 (en) * | 1996-06-06 | 2003-03-06 | Crooke Stanley T. | Human RNase III and compositions and uses thereof |
US20040161777A1 (en) * | 1996-06-06 | 2004-08-19 | Baker Brenda F. | Modified oligonucleotides for use in RNA interference |
US7812149B2 (en) | 1996-06-06 | 2010-10-12 | Isis Pharmaceuticals, Inc. | 2′-Fluoro substituted oligomeric compounds and compositions for use in gene modulations |
US9096636B2 (en) * | 1996-06-06 | 2015-08-04 | Isis Pharmaceuticals, Inc. | Chimeric oligomeric compounds and their use in gene modulation |
US20040171030A1 (en) * | 1996-06-06 | 2004-09-02 | Baker Brenda F. | Oligomeric compounds having modified bases for binding to cytosine and uracil or thymine and their use in gene modulation |
US20040171031A1 (en) * | 1996-06-06 | 2004-09-02 | Baker Brenda F. | Sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
US5807743A (en) * | 1996-12-03 | 1998-09-15 | Ribozyme Pharmaceuticals, Inc. | Interleukin-2 receptor gamma-chain ribozymes |
US6251666B1 (en) | 1997-03-31 | 2001-06-26 | Ribozyme Pharmaceuticals, Inc. | Nucleic acid catalysts comprising L-nucleotide analogs |
US6280936B1 (en) | 1997-06-09 | 2001-08-28 | Ribozyme Pharmaceuticals, Inc. | Method for screening nucleic acid catalysts |
US6548657B1 (en) | 1997-06-09 | 2003-04-15 | Ribozyme Pharmaceuticals, Inc. | Method for screening nucleic acid catalysts |
US6656731B1 (en) | 1997-09-22 | 2003-12-02 | Max Planck Gesellschaft Zur Forderung Der Wissenschaften E.V. | Nucleic acid catalysts with endonuclease activity |
US6127173A (en) * | 1997-09-22 | 2000-10-03 | Ribozyme Pharmaceuticals, Inc. | Nucleic acid catalysts with endonuclease activity |
US6420115B1 (en) | 1999-12-21 | 2002-07-16 | Ingeneus Corporation | Cation mediated triplex hybridization assay |
US6403313B1 (en) | 1999-12-21 | 2002-06-11 | Ingeneus Corporation | Fluorescent intensity assay for duplex and triplex nucleic acid hybridization solution utilizing fluorescent intercalators |
US6858390B2 (en) | 1998-12-31 | 2005-02-22 | Ingeneus Corporation | Aptamers containing sequences of nucleic acid or nucleic acid analogues bound homologously, or in novel complexes |
US6656692B2 (en) | 1999-12-21 | 2003-12-02 | Ingeneus Corporation | Parallel or antiparallel, homologous or complementary binding of nucleic acids or analogues thereof to form duplex, triplex or quadruplex complexes |
US20030181412A1 (en) * | 1999-12-21 | 2003-09-25 | Ingeneus Corporation | Method for modifying transcription and/or translation in an organism for therapeutic, prophylactic and/or analytic uses |
US6924108B2 (en) | 1999-12-21 | 2005-08-02 | Ingeneus Corporation | Nucleic acid binding enhancement by conjugation with nucleotides, nucleosides, bases and/or their analogues |
US6911536B1 (en) | 1999-12-21 | 2005-06-28 | Ingeneus Corporation | Triplex and quadruplex catalytic hybridization |
US7309569B2 (en) | 1999-12-21 | 2007-12-18 | Ingeneus, Inc. | Parallel or antiparallel, homologous or complementary binding of nucleic acids or analogues thereof to form duplex, triplex or quadruplex complexes |
US6927027B2 (en) | 1999-12-21 | 2005-08-09 | Ingeneus Corporation | Nucleic acid multiplex formation |
US7052844B2 (en) * | 1999-12-21 | 2006-05-30 | Ingeneus, Inc. | Purification of DS-DNA using heteropolymeric capture probes and a triplex, quadruplex or homologous duplex binding mechanism |
US6982147B2 (en) * | 2000-01-24 | 2006-01-03 | Ingeneus Corporation | Apparatus for assaying biopolymer binding by means of multiple measurements under varied conditions |
US7220541B2 (en) | 2000-01-24 | 2007-05-22 | Ingeneus, Inc. | Homogeneous assay of biopolymer binding by means of multiple measurements under varied conditions |
US20030170659A1 (en) * | 2000-01-24 | 2003-09-11 | Ingeneus Corporation | Electrical treatment of binding media to encourage, discourage and/or study biopolymer binding |
US6613524B1 (en) | 2000-01-24 | 2003-09-02 | Ingeneus Corporation | Amperometric affinity assay and electrically stimulated complexes of nucleic acids |
US6831171B2 (en) | 2000-02-08 | 2004-12-14 | Yale University | Nucleic acid catalysts with endonuclease activity |
US20050233329A1 (en) * | 2002-02-20 | 2005-10-20 | Sirna Therapeutics, Inc. | Inhibition of gene expression using duplex forming oligonucleotides |
US7491805B2 (en) | 2001-05-18 | 2009-02-17 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
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 |
US20050032733A1 (en) * | 2001-05-18 | 2005-02-10 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (SiNA) |
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) |
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 |
CA2398282A1 (en) * | 2000-02-11 | 2001-08-16 | Ribozyme Pharmaceuticals, Inc. | Method and reagent for the modulation and diagnosis of cd20 and nogo gene expression |
US7833992B2 (en) | 2001-05-18 | 2010-11-16 | Merck Sharpe & Dohme | Conjugates and compositions for cellular delivery |
US20080039414A1 (en) * | 2002-02-20 | 2008-02-14 | Sima Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US7102024B1 (en) * | 2000-08-01 | 2006-09-05 | Schwartz David A | Functional biopolymer modification reagents and uses thereof |
US8568766B2 (en) | 2000-08-24 | 2013-10-29 | Gattadahalli M. Anantharamaiah | Peptides and peptide mimetics to treat pathologies associated with eye disease |
US20050209179A1 (en) * | 2000-08-30 | 2005-09-22 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA) |
US20080032942A1 (en) * | 2000-08-30 | 2008-02-07 | Mcswiggen James | RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA) |
AU2001286959B2 (en) | 2000-09-01 | 2007-09-06 | Ribozyme Pharmaceuticals, Incorporated | Methods for synthesizing nucleosides, nucleoside derivatives and non-nucleoside derivatives |
US20020150936A1 (en) * | 2000-09-01 | 2002-10-17 | Leonid Beigelman | Methods for synthesizing nucleosides, nucleoside derivatives and non-nucleoside derivatives |
US7125660B2 (en) | 2000-09-13 | 2006-10-24 | Archemix Corp. | Nucleic acid sensor molecules and methods of using same |
AU2001290965A1 (en) * | 2000-09-13 | 2002-03-26 | Archemix Corporation | Target activated nucleic acid biosensor and methods of using same |
US20020165192A1 (en) * | 2000-09-19 | 2002-11-07 | Kerr William G. | Control of NK cell function and survival by modulation of ship activity |
US20110052546A1 (en) * | 2000-09-19 | 2011-03-03 | University Of South Florida | Inhibition of SHIP to Enhance Stem Cell Harvest and Transplantation |
WO2009042910A2 (en) * | 2007-09-26 | 2009-04-02 | University Of South Florida | Ship inhibition to direct hematopoietic stem cells and induce extramedullary hematopoiesis |
AU2001296846B2 (en) | 2000-10-12 | 2007-07-05 | University Of Rochester | Compositions that inhibit proliferation of cancer cells |
US20050222066A1 (en) * | 2001-05-18 | 2005-10-06 | 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) |
US20050182006A1 (en) * | 2001-05-18 | 2005-08-18 | Sirna Therapeutics, Inc | RNA interference mediated inhibition of protein kinase C alpha (PKC-alpha) gene expression using short interfering nucleic acid (siNA) |
US20040006035A1 (en) * | 2001-05-29 | 2004-01-08 | Dennis Macejak | Nucleic acid mediated disruption of HIV fusogenic peptide interactions |
US20050164967A1 (en) * | 2001-05-18 | 2005-07-28 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of platelet-derived endothelial cell growth factor (ECGF1) gene expression using short interfering nucleic acid (siNA) |
US20060142225A1 (en) * | 2001-05-18 | 2006-06-29 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of cyclin dependent kinase-2 (CDK2) gene expression using short interfering nucleic acid (siNA) |
US20050191638A1 (en) * | 2002-02-20 | 2005-09-01 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA) |
US20050182007A1 (en) * | 2001-05-18 | 2005-08-18 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA) |
US20050054596A1 (en) * | 2001-11-30 | 2005-03-10 | Mcswiggen James | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20050159380A1 (en) * | 2001-05-18 | 2005-07-21 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of angiopoietin gene expression using short interfering nucleic acid (siNA) |
US20060211642A1 (en) * | 2001-05-18 | 2006-09-21 | Sirna Therapeutics, Inc. | RNA inteference mediated inhibition of hepatitis C virus (HVC) gene expression using short interfering nucleic acid (siNA) |
US20050196765A1 (en) * | 2001-05-18 | 2005-09-08 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of checkpoint Kinase-1 (CHK-1) gene expression using short interfering nucleic acid (siNA) |
US20050256068A1 (en) * | 2001-05-18 | 2005-11-17 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of stearoyl-CoA desaturase (SCD) gene expression using short interfering nucleic acid (siNA) |
US20050143333A1 (en) * | 2001-05-18 | 2005-06-30 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA) |
JP4358521B2 (ja) | 2001-05-18 | 2009-11-04 | サーナ・セラピューティクス・インコーポレイテッド | 細胞デリバリーのためのコンジュゲートおよび組成物 |
US20050164224A1 (en) * | 2001-05-18 | 2005-07-28 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of cyclin D1 gene expression using short interfering nucleic acid (siNA) |
US20050233344A1 (en) * | 2001-05-18 | 2005-10-20 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of platelet derived growth factor (PDGF) and platelet derived growth factor receptor (PDGFR) gene expression using short interfering nucleic acid (siNA) |
US20050080031A1 (en) * | 2001-05-18 | 2005-04-14 | Sirna Therapeutics, Inc. | Nucleic acid treatment of diseases or conditions related to levels of Ras, HER2 and HIV |
US20050182009A1 (en) * | 2001-05-18 | 2005-08-18 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of NF-Kappa B / REL-A gene expression using short interfering nucleic acid (siNA) |
US20050288242A1 (en) * | 2001-05-18 | 2005-12-29 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of RAS gene expression using short interfering nucleic acid (siNA) |
US20050130181A1 (en) * | 2001-05-18 | 2005-06-16 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of wingless gene expression using short interfering nucleic acid (siNA) |
US20060019913A1 (en) * | 2001-05-18 | 2006-01-26 | Sirna Therapeutics, Inc. | RNA interference mediated inhibtion of protein tyrosine phosphatase-1B (PTP-1B) gene expression using short interfering nucleic acid (siNA) |
US20050176666A1 (en) * | 2001-05-18 | 2005-08-11 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of GPRA and AAA1 gene expression using short interfering nucleic acid (siNA) |
US20050159379A1 (en) * | 2001-05-18 | 2005-07-21 | Sirna Therapeutics, Inc | RNA interference mediated inhibition of gastric inhibitory polypeptide (GIP) and gastric inhibitory polypeptide receptor (GIPR) gene expression using short interfering nucleic acid (siNA) |
US20050124568A1 (en) * | 2001-05-18 | 2005-06-09 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of acetyl-CoA-carboxylase gene expression using short interfering nucleic acid (siNA) |
US7517864B2 (en) * | 2001-05-18 | 2009-04-14 | 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) |
US20050233996A1 (en) * | 2002-02-20 | 2005-10-20 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of hairless (HR) 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) |
US20070042983A1 (en) * | 2001-05-18 | 2007-02-22 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA) |
US20070270579A1 (en) * | 2001-05-18 | 2007-11-22 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA) |
US20050124567A1 (en) * | 2001-05-18 | 2005-06-09 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of TRPM7 gene expression using short interfering nucleic acid (siNA) |
US20050209180A1 (en) * | 2001-05-18 | 2005-09-22 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of hepatitis C virus (HCV) expression using short interfering nucleic acid (siNA) |
US20060241075A1 (en) * | 2001-05-18 | 2006-10-26 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of desmoglein gene expression using short interfering nucleic acid (siNA) |
US20050164968A1 (en) * | 2001-05-18 | 2005-07-28 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of ADAM33 gene expression using short interfering nucleic acid (siNA) |
US20050164966A1 (en) * | 2001-05-18 | 2005-07-28 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of type 1 insulin-like growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20050187174A1 (en) * | 2001-05-18 | 2005-08-25 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of intercellular adhesion molecule (ICAM) gene expression using short interfering nucleic acid (siNA) |
US20050119211A1 (en) * | 2001-05-18 | 2005-06-02 | Sirna Therapeutics, Inc. | RNA mediated inhibition connexin gene expression using short interfering nucleic acid (siNA) |
US20050014172A1 (en) * | 2002-02-20 | 2005-01-20 | Ivan Richards | RNA interference mediated inhibition of muscarinic cholinergic receptor gene expression using short interfering nucleic acid (siNA) |
US20060142226A1 (en) * | 2001-05-18 | 2006-06-29 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of cholesteryl ester transfer protein (CETP) gene expression using short interfering nucleic acid (siNA) |
US20050159382A1 (en) * | 2001-05-18 | 2005-07-21 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of polycomb group protein EZH2 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 |
US20050153915A1 (en) * | 2001-05-18 | 2005-07-14 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of early growth response gene expression using short interfering nucleic acid (siNA) |
US20050137155A1 (en) * | 2001-05-18 | 2005-06-23 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of Parkinson disease using short interfering nucleic acid (siNA) |
US20050282188A1 (en) * | 2001-05-18 | 2005-12-22 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA) |
US20050079610A1 (en) * | 2001-05-18 | 2005-04-14 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of Fos gene expression using short interfering nucleic acid (siNA) |
US20050227935A1 (en) * | 2001-05-18 | 2005-10-13 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of TNF and TNF receptor gene expression using short interfering nucleic acid (siNA) |
US20050136436A1 (en) * | 2001-05-18 | 2005-06-23 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of G72 and D-amino acid oxidase (DAAO) gene expression using short interfering nucleic acid (siNA) |
US20050176664A1 (en) * | 2001-05-18 | 2005-08-11 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of cholinergic muscarinic receptor (CHRM3) gene expression using short interfering nucleic acid (siNA) |
US20040219671A1 (en) * | 2002-02-20 | 2004-11-04 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of parkinson disease using short interfering nucleic acid (siNA) |
US20050119212A1 (en) * | 2001-05-18 | 2005-06-02 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of FAS and FASL gene expression using short interfering nucleic acid (siNA) |
US20050124566A1 (en) * | 2001-05-18 | 2005-06-09 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of myostatin gene expression using short interfering nucleic acid (siNA) |
US20050287128A1 (en) * | 2001-05-18 | 2005-12-29 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of TGF-beta and TGF-beta receptor gene expression using short interfering nucleic acid (siNA) |
US20050196767A1 (en) * | 2001-05-18 | 2005-09-08 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of GRB2 associated binding protein (GAB2) gene expression using short interfering nucleic acis (siNA) |
US20050267058A1 (en) * | 2001-05-18 | 2005-12-01 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (sINA) |
US20080188430A1 (en) * | 2001-05-18 | 2008-08-07 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of hypoxia inducible factor 1 (HIF1) gene expression using short interfering nucleic acid (siNA) |
US20050054598A1 (en) * | 2002-02-20 | 2005-03-10 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition hairless (HR) gene expression using short interfering nucleic acid (siNA) |
US20050233997A1 (en) * | 2001-05-18 | 2005-10-20 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of matrix metalloproteinase 13 (MMP13) gene expression using short interfering nucleic acid (siNA) |
US20050203040A1 (en) * | 2001-05-18 | 2005-09-15 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of vascular cell adhesion molecule (VCAM) gene expression using short interfering nucleic acid (siNA) |
US20080161256A1 (en) * | 2001-05-18 | 2008-07-03 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA) |
US20040198682A1 (en) * | 2001-11-30 | 2004-10-07 | Mcswiggen James | RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (siNA) |
US20050159376A1 (en) * | 2002-02-20 | 2005-07-21 | Slrna Therapeutics, Inc. | RNA interference mediated inhibition 5-alpha reductase and androgen receptor gene expression using short interfering nucleic acid (siNA) |
US9994853B2 (en) | 2001-05-18 | 2018-06-12 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
US20040209831A1 (en) * | 2002-02-20 | 2004-10-21 | Mcswiggen James | RNA interference mediated inhibition of hepatitis C virus (HCV) gene expression using short interfering nucleic acid (siNA) |
US20050153914A1 (en) * | 2001-05-18 | 2005-07-14 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of MDR P-glycoprotein gene expression using short interfering nucleic acid (siNA) |
US20050176665A1 (en) * | 2001-05-18 | 2005-08-11 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of hairless (HR) gene expression using short interfering nucleic acid (siNA) |
US7785610B2 (en) * | 2001-06-21 | 2010-08-31 | Dynavax Technologies Corporation | Chimeric immunomodulatory compounds and methods of using the same—III |
US7255868B2 (en) * | 2001-06-21 | 2007-08-14 | Dynavax Technologies Corporation | Chimeric immunomodulatory compounds and methods of using the same—I |
US20040126867A1 (en) * | 2001-07-06 | 2004-07-01 | Crooke Stanley T. | Human RNase III and compositions and uses thereof |
DE10150121B4 (de) * | 2001-10-11 | 2005-12-01 | Bernhard-Nocht-Institut für Tropenmedizin | Echtzeitdetektion von DNA-Amplifikationsprodukten |
US20050075304A1 (en) * | 2001-11-30 | 2005-04-07 | Mcswiggen James | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20040138163A1 (en) * | 2002-05-29 | 2004-07-15 | Mcswiggen James | RNA interference mediated inhibition of vascular edothelial growth factor and vascular edothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20070203333A1 (en) * | 2001-11-30 | 2007-08-30 | Mcswiggen James | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
EP1572902B1 (en) * | 2002-02-01 | 2014-06-11 | Life Technologies Corporation | HIGH POTENCY siRNAS FOR REDUCING THE EXPRESSION OF TARGET GENES |
CA2474910A1 (en) | 2002-02-01 | 2003-08-07 | Sequitur, Inc. | Oligonucleotide compositions with enhanced efficiency |
US20060009409A1 (en) | 2002-02-01 | 2006-01-12 | Woolf Tod M | Double-stranded oligonucleotides |
EP2311852A1 (en) | 2002-02-06 | 2011-04-20 | Stasys Technologies, Inc. | Anti-infarction molecules |
WO2003106476A1 (en) * | 2002-02-20 | 2003-12-24 | Sirna Therapeutics, Inc | Nucleic acid mediated inhibition of enterococcus infection and cytolysin toxin activity |
US20050137153A1 (en) * | 2002-02-20 | 2005-06-23 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of alpha-1 antitrypsin (AAT) gene expression using 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) |
AU2003211058A1 (en) * | 2002-02-20 | 2003-09-09 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED TARGET DISCOVERY AND TARGET VALIDATION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
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) |
US20050096284A1 (en) * | 2002-02-20 | 2005-05-05 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA) |
EP1432724A4 (en) | 2002-02-20 | 2006-02-01 | Sirna Therapeutics Inc | RNA inhibition mediated inhibition of MAP KINASE GENES |
US20050222064A1 (en) * | 2002-02-20 | 2005-10-06 | Sirna Therapeutics, Inc. | Polycationic compositions for cellular delivery of polynucleotides |
WO2003093452A2 (en) * | 2002-02-26 | 2003-11-13 | University Of Utah Research Foundation | Variants of nedd4l associated with hypertension and viral budding |
AU2003276666A1 (en) * | 2002-06-12 | 2003-12-31 | Ambion, Inc. | Methods and compositions relating to polypeptides with rnase iii domains that mediate rna interference |
US20100075423A1 (en) * | 2002-06-12 | 2010-03-25 | Life Technologies Corporation | Methods and compositions relating to polypeptides with rnase iii domains that mediate rna interference |
US20040248094A1 (en) * | 2002-06-12 | 2004-12-09 | Ford Lance P. | Methods and compositions relating to labeled RNA molecules that reduce gene expression |
CN1688716A (zh) * | 2002-06-28 | 2005-10-26 | 罗斯塔英法美蒂克斯有限责任公司 | 评估微阵列质量的方法 |
US6989442B2 (en) * | 2002-07-12 | 2006-01-24 | Sirna Therapeutics, Inc. | Deprotection and purification of oligonucleotides and their derivatives |
US7655790B2 (en) | 2002-07-12 | 2010-02-02 | Sirna Therapeutics, Inc. | Deprotection and purification of oligonucleotides and their derivatives |
WO2004013160A2 (en) | 2002-08-05 | 2004-02-12 | University Of Rochester | Protein transducing domain/deaminase chimeric proteins, related compounds, and uses thereof |
WO2004015075A2 (en) * | 2002-08-08 | 2004-02-19 | Dharmacon, Inc. | Short interfering rnas having a hairpin structure containing a non-nucleotide loop |
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 |
EP1551376A4 (en) | 2002-08-12 | 2010-10-06 | Dynavax Tech Corp | IMMUNOMODULATORY COMPOSITIONS, THEIR METHODS OF PREPARATION AND USE |
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) |
US20080214437A1 (en) * | 2002-09-06 | 2008-09-04 | Mohapatra Shyam S | Methods and compositions for reducing activity of the atrial natriuretic peptide receptor and for treatment of diseases |
WO2004022003A2 (en) | 2002-09-06 | 2004-03-18 | University Of South Florida | Materials and methods for treatment of allergic diseases |
JP2006508927A (ja) * | 2002-09-19 | 2006-03-16 | メルク エンド カムパニー インコーポレーテッド | エストロゲン受容体修飾因子 |
US20040242518A1 (en) * | 2002-09-28 | 2004-12-02 | Massachusetts Institute Of Technology | Influenza therapeutic |
EP1560839A4 (en) | 2002-11-05 | 2008-04-23 | Isis Pharmaceuticals Inc | CHIMERIC OLIGOMER COMPOUNDS AND THEIR USE IN GENE MODULATION |
EP1578765A4 (en) | 2002-11-05 | 2008-04-23 | Isis Pharmaceuticals Inc | OLIGOMERIC COMPOUNDS CONTAINING SUGAR SUBSTITUTE AND COMPOSITIONS FOR USE IN GENE MODULATION |
US20040231231A1 (en) * | 2002-12-20 | 2004-11-25 | Cataldo Dominic A. | Use of colloidal clays for sustained release of active ingredients |
US7625872B2 (en) * | 2002-12-23 | 2009-12-01 | Dynavax Technologies Corporation | Branched immunomodulatory compounds and methods of using the same |
EP1620112A4 (en) * | 2003-04-17 | 2007-04-25 | Univ Columbia | DESMOGLEIN 4 IS A NEW GENUS INVOLVED IN HAIR GROWTH |
EP1622572B1 (en) | 2003-04-30 | 2017-12-20 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
EP1636342A4 (en) * | 2003-06-20 | 2008-10-08 | Isis Pharmaceuticals Inc | OLIGOMERIC COMPOUNDS FOR GENE MODULATION |
US7807646B1 (en) * | 2003-11-20 | 2010-10-05 | University Of South Florida | SHIP-deficiency to increase megakaryocyte progenitor production |
CA2559853A1 (en) * | 2004-02-17 | 2005-10-13 | University Of South Florida | Materials and methods for treatment of inflammatory and cell proliferation disorders |
CN1918293A (zh) * | 2004-02-20 | 2007-02-21 | 莫洛根股份公司 | 用于对人及高等动物进行治疗性和预防性免疫刺激的取代的非编码核酸分子 |
US8569474B2 (en) | 2004-03-09 | 2013-10-29 | Isis Pharmaceuticals, Inc. | Double stranded constructs comprising one or more short strands hybridized to a longer strand |
AU2005230684B2 (en) * | 2004-04-05 | 2011-10-06 | Alnylam Pharmaceuticals, Inc. | Process and reagents for oligonucleotide synthesis and purification |
WO2005105157A2 (en) | 2004-04-23 | 2005-11-10 | The Trustees Of Columbia University In The City Ofnew York | INHIBITION OF HAIRLESS PROTEIN mRNA |
JP4584986B2 (ja) * | 2004-04-27 | 2010-11-24 | アルニラム ファーマスーティカルズ インコーポレイテッド | 2−アリールプロピル部分を含む1本鎖及び2本鎖オリゴヌクレオチド |
JP4584987B2 (ja) * | 2004-04-30 | 2010-11-24 | アルニラム ファーマスーティカルズ インコーポレイテッド | C5修飾ピリミジンを含むオリゴヌクレオチド |
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 |
US10508277B2 (en) | 2004-05-24 | 2019-12-17 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
WO2005121372A2 (en) * | 2004-06-03 | 2005-12-22 | Isis Pharmaceuticals, Inc. | Double strand compositions comprising differentially modified strands for use in gene modulation |
US8394947B2 (en) | 2004-06-03 | 2013-03-12 | Isis Pharmaceuticals, Inc. | Positionally modified siRNA constructs |
WO2006088490A2 (en) * | 2004-06-30 | 2006-08-24 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising a non-phosphate backbone linkage |
CA2574088C (en) | 2004-07-21 | 2013-09-17 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising a modified or non-natural nucleobase |
US7632932B2 (en) | 2004-08-04 | 2009-12-15 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising a ligand tethered to a modified or non-natural nucleobase |
PT1794174E (pt) | 2004-09-01 | 2012-08-16 | Dynavax Tech Corp | Métodos e composições para inibição de respostas imunitárias inatas e auto-imunidade |
US7884086B2 (en) | 2004-09-08 | 2011-02-08 | Isis Pharmaceuticals, Inc. | Conjugates for use in hepatocyte free uptake assays |
EP1836218A2 (en) * | 2004-12-17 | 2007-09-26 | Dynavax Technologies Corporation | Methods and compositions for induction or promotion of immune tolerance |
US20060142228A1 (en) * | 2004-12-23 | 2006-06-29 | Ambion, Inc. | Methods and compositions concerning siRNA's as mediators of RNA interference |
AU2006210838B2 (en) | 2005-02-02 | 2011-10-20 | The Uab Research Foundation | Agents and methods related to reducing resistance to apoptosis-inducing death receptor agonists |
EP3153525A1 (en) | 2005-03-23 | 2017-04-12 | Genmab A/S | Antibodies against cd38 for treatment of multiple myeloma |
US7476733B2 (en) * | 2005-03-25 | 2009-01-13 | The United States Of America As Represented By The Department Of Health And Human Services | Development of a real-time PCR assay for detection of pneumococcal DNA and diagnosis of pneumococccal disease |
US20090203055A1 (en) * | 2005-04-18 | 2009-08-13 | Massachusetts Institute Of Technology | Compositions and methods for RNA interference with sialidase expression and uses thereof |
WO2006138145A1 (en) | 2005-06-14 | 2006-12-28 | Northwestern University | Nucleic acid functionalized nanoparticles for therapeutic applications |
US8115716B2 (en) | 2005-08-04 | 2012-02-14 | Sharp Kabushiki Kaisha | Liquid crystal display device and its drive method |
US20090176725A1 (en) * | 2005-08-17 | 2009-07-09 | Sirna Therapeutics Inc. | Chemically modified short interfering nucleic acid molecules that mediate rna interference |
CA2625349A1 (en) * | 2005-10-06 | 2007-04-19 | Emthrax, Llc | Methods and compositions relating to anthrax spore glycoproteins as vaccines |
US8080534B2 (en) | 2005-10-14 | 2011-12-20 | Phigenix, Inc | Targeting PAX2 for the treatment of breast cancer |
CA2625891A1 (en) | 2005-10-14 | 2007-04-26 | Carlton D. Donald | Inhibition of pax2 by defb1 induction as a therapy for cancer |
EP2051585A4 (en) * | 2006-04-28 | 2010-06-02 | Univ South Florida | MATERIALS AND METHODS OF SUPPRESSING INFLAMMATION THROUGH INHIBITION OF THE VORHOF RECEPTOR FOR NATRIURETIC PEPTIDES |
WO2007127439A2 (en) | 2006-04-28 | 2007-11-08 | Children's Hospital Medical Center | Compositions comprising fusogenic proteins or polypeptides derived from prosaposin for application in transmembrane drug delivery systems |
CA2981308C (en) | 2006-09-21 | 2020-12-22 | University Of Rochester | Compositions and methods related to protein displacement therapy for myotonic dystrophy |
EP2104516B1 (en) | 2006-11-01 | 2015-01-07 | University of Rochester | Methods and compositions related to the structure and function of apobec3g |
KR20090089462A (ko) | 2006-12-11 | 2009-08-21 | 유니버시티 오브 유타 리써치 파운데이션 | 병적 혈관형성 및 혈관 투과성을 치료하기 위한 조성물 및 방법 |
US7951789B2 (en) | 2006-12-28 | 2011-05-31 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
MX2009008470A (es) | 2007-02-09 | 2009-11-26 | Univ Northwestern | Particulas para detectar objetivos intracelulares. |
JP2010519256A (ja) | 2007-02-23 | 2010-06-03 | ザ・トラスティーズ・オブ・コランビア・ユニバーシティー・イン・ザ・シティー・オブ・ニューヨーク | 免疫疾患を治療するために、HLA−E/Qa−1拘束性CD8+T細胞制御性経路を活性化または遮断する方法 |
US20100292301A1 (en) * | 2007-02-28 | 2010-11-18 | Elena Feinstein | Novel sirna structures |
DK2494993T3 (en) | 2007-05-04 | 2018-11-12 | Marina Biotech Inc | Amino acid lipids and uses thereof |
CA2689923A1 (en) | 2007-05-30 | 2008-12-11 | Northwestern University | Nucleic acid functionalized nanoparticles for therapeutic applications |
CA2697957A1 (en) | 2007-08-28 | 2009-03-12 | Uab Research Foundation | Synthetic apolipoprotein e mimicking polypeptides and methods of use |
EP2195331B1 (en) | 2007-08-28 | 2013-11-20 | Uab Research Foundation | Synthetic apolipoprotein e mimicking polypeptides and methods of use |
WO2009044392A2 (en) * | 2007-10-03 | 2009-04-09 | Quark Pharmaceuticals, Inc. | Novel sirna structures |
AU2008317261B2 (en) | 2007-10-26 | 2015-04-09 | Dynavax Technologies Corporation | Methods and compositions for inhibition of immune responses and autoimmunity |
CA2706317C (en) * | 2007-12-03 | 2017-06-13 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Doc1 compositions and methods for treating cancer |
US8614311B2 (en) | 2007-12-12 | 2013-12-24 | Quark Pharmaceuticals, Inc. | RTP801L siRNA compounds and methods of use thereof |
US20110105584A1 (en) * | 2007-12-12 | 2011-05-05 | Elena Feinstein | Rtp80il sirna compounds and methods of use thereof |
WO2009090639A2 (en) * | 2008-01-15 | 2009-07-23 | Quark Pharmaceuticals, Inc. | Sirna compounds and methods of use thereof |
CN104975020B (zh) | 2008-02-11 | 2020-01-17 | 菲奥医药公司 | 经修饰的RNAi多核苷酸及其用途 |
US20090233993A1 (en) * | 2008-03-06 | 2009-09-17 | Burnham Institute For Medical Research | Compositions and methods for inhibiting gsk3 activity and uses thereof |
AU2009227549A1 (en) * | 2008-03-20 | 2009-09-24 | Quark Pharmaceuticals, Inc. | Novel siRNA compounds for inhibiting RTP801 |
EP2285385A4 (en) * | 2008-04-15 | 2013-01-16 | Quark Pharmaceuticals Inc | COMPOUNDS BASED ON RNSI TO INHIBIT NRF2 |
US20110229498A1 (en) | 2008-05-08 | 2011-09-22 | The Johns Hopkins University | Compositions and methods for modulating an immune response |
EP2853897A1 (en) | 2008-05-08 | 2015-04-01 | University Of Utah Research Foundation | Sensory receptors for chronic fatigue and pain and uses thereof |
JP2011521649A (ja) | 2008-05-30 | 2011-07-28 | イェール ユニバーシティー | 遺伝子発現を改変するための標的化オリゴヌクレオチド組成物 |
KR20110065440A (ko) * | 2008-07-02 | 2011-06-15 | 아이데닉스 파마슈티칼스, 인코포레이티드 | 바이러스 감염의 치료를 위한 화합물 및 제약 조성물 |
US8815818B2 (en) | 2008-07-18 | 2014-08-26 | Rxi Pharmaceuticals Corporation | Phagocytic cell delivery of RNAI |
CN108165548B (zh) | 2008-09-22 | 2022-10-14 | 菲奥医药公司 | 减小大小的自递送RNAi化合物 |
JP2012505913A (ja) | 2008-10-16 | 2012-03-08 | マリーナ バイオテック,インコーポレイテッド | 遺伝子発現を抑制する治療におけるリポソームによる効率的な送達のプロセスおよび組成物 |
US9074211B2 (en) | 2008-11-19 | 2015-07-07 | Rxi Pharmaceuticals Corporation | Inhibition of MAP4K4 through RNAI |
WO2010060110A1 (en) | 2008-11-24 | 2010-05-27 | Northwestern University | Polyvalent rna-nanoparticle compositions |
WO2010065617A1 (en) | 2008-12-02 | 2010-06-10 | University Of Utah Research Foundation | Pde1 as a target therapeutic in heart disease |
WO2010078536A1 (en) | 2009-01-05 | 2010-07-08 | Rxi Pharmaceuticals Corporation | Inhibition of pcsk9 through rnai |
US20100233270A1 (en) | 2009-01-08 | 2010-09-16 | Northwestern University | Delivery of Oligonucleotide-Functionalized Nanoparticles |
WO2010090762A1 (en) | 2009-02-04 | 2010-08-12 | Rxi Pharmaceuticals Corporation | Rna duplexes with single stranded phosphorothioate nucleotide regions for additional functionality |
US20110038871A1 (en) | 2009-08-11 | 2011-02-17 | Veena Viswanth | Ccr2 inhibitors for treating conditions of the eye |
WO2011031974A1 (en) | 2009-09-10 | 2011-03-17 | Southern Research Institute | Acridine analogs in the treatment of gliomas |
JP5866119B2 (ja) | 2009-10-30 | 2016-02-17 | ノースウェスタン ユニバーシティ | 鋳型ナノ複合体 |
ES2759003T3 (es) | 2009-11-26 | 2020-05-07 | Quark Pharmaceuticals Inc | Compuestos de ARNip que comprenden sustituciones terminales |
CN102741410B (zh) | 2009-12-09 | 2016-11-16 | 日东电工株式会社 | Hsp47表达的调节 |
WO2011084193A1 (en) | 2010-01-07 | 2011-07-14 | Quark Pharmaceuticals, Inc. | Oligonucleotide compounds comprising non-nucleotide overhangs |
US20110207789A1 (en) | 2010-02-19 | 2011-08-25 | Ye Fang | Methods related to casein kinase ii (ck2) inhibitors and the use of purinosome-disrupting ck2 inhibitors for anti-cancer therapy agents |
WO2011119871A1 (en) | 2010-03-24 | 2011-09-29 | Rxi Phrmaceuticals Corporation | Rna interference in ocular indications |
CN110042099A (zh) | 2010-03-24 | 2019-07-23 | 菲奥医药公司 | 皮肤与纤维化症候中的rna干扰 |
US9080171B2 (en) | 2010-03-24 | 2015-07-14 | RXi Parmaceuticals Corporation | Reduced size self-delivering RNAi compounds |
WO2011120023A1 (en) | 2010-03-26 | 2011-09-29 | Marina Biotech, Inc. | Nucleic acid compounds for inhibiting survivin gene expression uses thereof |
US8680071B2 (en) | 2010-04-01 | 2014-03-25 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2011130371A1 (en) | 2010-04-13 | 2011-10-20 | Life Technologies Corporation | Compositions and methods for inhibition of nucleic acids function |
WO2011133584A2 (en) | 2010-04-19 | 2011-10-27 | Marina Biotech, Inc. | Nucleic acid compounds for inhibiting hras gene expression and uses thereof |
WO2011139710A1 (en) | 2010-04-26 | 2011-11-10 | Marina Biotech, Inc. | Nucleic acid compounds with conformationally restricted monomers and uses thereof |
WO2011139843A2 (en) | 2010-04-28 | 2011-11-10 | Marina Biotech, Inc. | Multi-sirna compositions for reducing gene expression |
CA2802873C (en) | 2010-06-16 | 2018-09-18 | Dynavax Technologies Corporation | Methods of treatment using tlr7 and/or tlr9 inhibitors |
CN103140582A (zh) | 2010-08-24 | 2013-06-05 | 默沙东公司 | 含有内部非核酸间隔子的单链RNAi试剂 |
EP3327125B1 (en) | 2010-10-29 | 2020-08-05 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of gene expression using short interfering nucleic acids (sina) |
US9205100B2 (en) | 2011-03-03 | 2015-12-08 | Quark Pharmaceuticals, Inc. | Compositions and methods for treating lung disease and injury |
US10184942B2 (en) | 2011-03-17 | 2019-01-22 | University Of South Florida | Natriuretic peptide receptor as a biomarker for diagnosis and prognosis of cancer |
CN103842369A (zh) | 2011-03-31 | 2014-06-04 | 埃迪尼克斯医药公司 | 用于治疗病毒感染的化合物和药物组合物 |
US10196637B2 (en) | 2011-06-08 | 2019-02-05 | Nitto Denko Corporation | Retinoid-lipid drug carrier |
TWI658830B (zh) | 2011-06-08 | 2019-05-11 | 日東電工股份有限公司 | Hsp47表現調控強化用類視色素脂質體 |
SG11201401314PA (en) | 2011-09-07 | 2014-09-26 | Marina Biotech Inc | Synthesis and uses of nucleic acid compounds with conformationally restricted monomers |
US9403863B2 (en) | 2011-09-12 | 2016-08-02 | Idenix Pharmaceuticals Llc | Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013040499A1 (en) | 2011-09-14 | 2013-03-21 | Northwestern University | Nanoconjugates able to cross the blood-brain barrier |
EP3597644B1 (en) | 2011-10-18 | 2021-09-29 | Dicerna Pharmaceuticals, Inc. | Amine cationic lipids and uses thereof |
AU2013280693B2 (en) | 2012-06-27 | 2018-01-04 | The Trustees Of Princeton University | Split inteins, conjugates and uses thereof |
AU2013291125A1 (en) | 2012-07-16 | 2015-01-22 | Dicerna Pharmaceuticals, Inc. | RNAi pharmaceutical composition capable of suppressing expression of KRAS gene |
WO2014043291A1 (en) | 2012-09-12 | 2014-03-20 | Quark Pharmaceuticals, Inc. | Double-stranded nucleic acid compounds |
US9228184B2 (en) | 2012-09-29 | 2016-01-05 | Dynavax Technologies Corporation | Human toll-like receptor inhibitors and methods of use thereof |
WO2014153163A1 (en) | 2013-03-14 | 2014-09-25 | Dicerna Pharmaceuticals, Inc. | Process for formulating an anionic agent |
WO2015027176A1 (en) * | 2013-08-22 | 2015-02-26 | Sony Corporation | Water soluble fluorescent or colored dyes and methods for their use |
EP3079707A4 (en) | 2013-12-02 | 2017-10-18 | RXi Pharmaceuticals Corporation | Immunotherapy of cancer |
LT3581654T (lt) | 2013-12-27 | 2021-06-25 | Dicerna Pharmaceuticals, Inc. | Būdai ir kompozicijos, skirti glikolato oksidazės (hao1) specifinei inhibicijai dvigrande rnr |
EP3137119B1 (en) | 2014-04-28 | 2020-07-01 | Phio Pharmaceuticals Corp. | Methods for treating cancer using a nucleic acid targeting mdm2 |
ES2725948T3 (es) | 2014-06-04 | 2019-09-30 | Exicure Inc | Suministro multivalente de inmunomoduladores mediante ácidos nucleicos esféricos liposomales para aplicaciones profilácticas o terapéuticas |
IL250302B (en) | 2014-07-31 | 2022-07-01 | Uab Research Foundation | Apoe mimetic peptides with high potency to clear plasma cholesterol |
US9932566B2 (en) | 2014-08-07 | 2018-04-03 | Agilent Technologies, Inc. | CIS-blocked guide RNA |
EP3188799B1 (en) | 2014-09-05 | 2022-07-06 | Phio Pharmaceuticals Corp. | Methods for treating aging and skin disorders using nucleic acids targeting tyr or mmp1 |
CN107106493A (zh) | 2014-11-21 | 2017-08-29 | 西北大学 | 球形核酸纳米颗粒缀合物的序列特异性细胞摄取 |
US10264976B2 (en) | 2014-12-26 | 2019-04-23 | The University Of Akron | Biocompatible flavonoid compounds for organelle and cell imaging |
CA2991598A1 (en) | 2015-07-06 | 2017-01-12 | Rxi Pharmaceuticals Corporation | Nucleic acid molecules targeting superoxide dismutase 1 (sod1) |
WO2017007825A1 (en) | 2015-07-06 | 2017-01-12 | Rxi Pharmaceuticals Corporation | Methods for treating neurological disorders using a synergistic small molecule and nucleic acids therapeutic approach |
LU92821B1 (en) | 2015-09-09 | 2017-03-20 | Mologen Ag | Combination comprising immunostimulatory oligonucleotides |
GB2542425A (en) | 2015-09-21 | 2017-03-22 | Mologen Ag | Means for the treatment of HIV |
JP2018531037A (ja) | 2015-10-19 | 2018-10-25 | アールエックスアイ ファーマシューティカルズ コーポレーション | 長い非コードrnaを標的とする減少したサイズの自己送達型核酸化合物 |
KR20180086260A (ko) | 2015-12-13 | 2018-07-30 | 닛토덴코 가부시키가이샤 | 높은 활성 및 감소한 오프 타겟을 위한 sirna 구조 |
AU2017213404A1 (en) | 2016-01-29 | 2018-09-20 | Kyowa Kirin Co., Ltd. | Nucleic acid conjugate |
CA3029508A1 (en) | 2016-06-30 | 2018-01-04 | Kyowa Hakko Kirin Co., Ltd. | Nucleic acid conjugate |
EP3491071A1 (en) | 2016-07-29 | 2019-06-05 | Sony Corporation | Ultra bright dimeric or polymeric dyes and methods for preparation of the same |
EP3496736A4 (en) | 2016-08-03 | 2020-05-13 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | THERAPEUTICS AGAINST TLR9 |
US11364304B2 (en) | 2016-08-25 | 2022-06-21 | Northwestern University | Crosslinked micellar spherical nucleic acids |
WO2019051355A1 (en) | 2017-09-08 | 2019-03-14 | Ohio State Innovation Foundation | NEW MICROARN INHIBITOR THERAPY FOR SYSTEMIC LUPUS ERYTHEMATOSUS |
PT3880212T (pt) | 2018-11-16 | 2024-02-08 | Nitto Denko Corp | Formulação e métodos de administração de rna de interferência para tumores malignos |
EP3888663A1 (en) | 2018-11-30 | 2021-10-06 | Kyowa Kirin Co., Ltd. | Nucleic acid complex |
BR112022018667A2 (pt) | 2020-03-18 | 2022-11-29 | Dicerna Pharmaceuticals Inc | Composições e métodos para inibir a expressão de ang-ptl3 |
EP4192478A2 (en) | 2020-08-04 | 2023-06-14 | Dicerna Pharmaceuticals, Inc. | Compositions and methods for inhibiting plp1 expression |
TW202221120A (zh) | 2020-08-04 | 2022-06-01 | 美商黛瑟納製藥公司 | 用於治療代謝症候群之組成物及方法 |
EP4192954A1 (en) | 2020-08-05 | 2023-06-14 | Dicerna Pharmaceuticals, Inc. | Compositions and methods for inhibiting lpa expression |
BR112023017367A2 (pt) | 2021-04-12 | 2023-12-12 | Boehringer Ingelheim Int | Composições e métodos para inibição de ceto-hexoquinase (khk) |
CA3209418A1 (en) | 2021-04-14 | 2022-10-20 | Utsav SAXENA | Compositions and methods for modulating pnpla3 expression |
MX2023012086A (es) | 2021-04-19 | 2023-10-25 | Novo Nordisk As | Composiciones y metodos para inhibir la expresion del miembro 3 del grupo h de la subfamilia 1 de receptores nucleares (nr1h3). |
EP4347820A1 (en) | 2021-05-28 | 2024-04-10 | Novo Nordisk A/S | Compositions and methods for inhibiting mitochondria amidoxime reducing component 1 (marc1) expression |
EP4392556A1 (en) | 2021-08-25 | 2024-07-03 | Dicerna Pharmaceuticals, Inc. | Compositions and methods for inhibiting ?lpha-1 antitrypsin expression |
US20230159930A1 (en) | 2021-11-19 | 2023-05-25 | Sanegene Bio Usa Inc. | Double stranded rna targeting angiopoietin-like 3 (angptl-3) and methods of use thereof |
KR20240111757A (ko) | 2021-12-01 | 2024-07-17 | 다이서나 파마수이티컬, 인크. | Apoc3 발현을 조절하기 위한 조성물 및 방법 |
AR129073A1 (es) | 2022-04-15 | 2024-07-10 | Dicerna Pharmaceuticals Inc | Composiciones y métodos para modular la actividad de scap |
US20240002857A1 (en) | 2022-05-09 | 2024-01-04 | Sanegene Bio Usa Inc. | Double stranded rna targeting 17-beta hydroxysteroiddehydrogenase 13 (hsd17b13) and methods of use thereof |
US20230416742A1 (en) | 2022-05-12 | 2023-12-28 | Dicerna Phrmaceuticals, Inc. | Compositions and methods for inhibiting mapt expression |
WO2023220351A1 (en) | 2022-05-13 | 2023-11-16 | Dicerna Pharmaceuticals, Inc. | Compositions and methods for inhibiting snca expression |
TW202400193A (zh) | 2022-06-24 | 2024-01-01 | 丹麥商諾佛 儂迪克股份有限公司 | 抑制跨膜絲胺酸蛋白酶6(tmprss6)表現的組成物及方法 |
US20240052348A1 (en) | 2022-08-05 | 2024-02-15 | Sanegene Bio Usa Inc. | Double stranded rna targeting angiotensinogen (agt) and methods of use thereof |
WO2024040041A1 (en) | 2022-08-15 | 2024-02-22 | Dicerna Pharmaceuticals, Inc. | Regulation of activity of rnai molecules |
WO2024079076A1 (en) | 2022-10-11 | 2024-04-18 | Boehringer Ingelheim International Gmbh | Methods for the treatment of nash with advanced fibrosis and/or cirrhosis |
US20240139230A1 (en) | 2022-10-11 | 2024-05-02 | Boehringer Ingelheim International Gmbh | Dosage regimen for the treatment of nash |
US20240175026A1 (en) | 2022-10-14 | 2024-05-30 | Sanegene Bio Usa Inc. | Small interfering rna targeting c3 and uses thereof |
WO2024107993A1 (en) | 2022-11-16 | 2024-05-23 | Dicerna Pharmaceuticals, Inc. | Stat3 targeting oligonucleotides and uses thereof |
WO2024137590A2 (en) | 2022-12-19 | 2024-06-27 | Sanegene Bio Usa Inc. | Small interfering rna targeting cfb and uses thereof |
WO2024137622A1 (en) | 2022-12-22 | 2024-06-27 | Eli Lilly And Company | Oligonucleotide fragments and methods of making rnai agents using the same |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4987071A (en) * | 1986-12-03 | 1991-01-22 | University Patents, Inc. | RNA ribozyme polymerases, dephosphorylases, restriction endoribonucleases and methods |
AU630076B2 (en) | 1987-09-21 | 1992-10-22 | Gen-Probe Incorporated | Non-nucleotide linking reagents for nucleotide probes |
CA1340323C (en) * | 1988-09-20 | 1999-01-19 | Arnold E. Hampel | Rna catalyst for cleaving specific rna sequences |
US5262530A (en) * | 1988-12-21 | 1993-11-16 | Applied Biosystems, Inc. | Automated system for polynucleotide synthesis and purification |
JP3058686B2 (ja) | 1989-08-31 | 2000-07-04 | シティ・オブ・ホープ | キメラdna―rna触媒活性配列 |
WO1991019789A1 (en) * | 1990-06-19 | 1991-12-26 | Commonwealth Scientific And Industrial Research Organisation | Endonucleases |
US6365730B1 (en) * | 1990-06-19 | 2002-04-02 | Gene Shears Pty. Limited | DNA-Armed ribozymes and minizymes |
DE69123979T2 (de) | 1990-10-12 | 1997-04-30 | Max Planck Gesellschaft | Abgeänderte ribozyme |
DE4216134A1 (de) * | 1991-06-20 | 1992-12-24 | Europ Lab Molekularbiolog | Synthetische katalytische oligonukleotidstrukturen |
US5652094A (en) * | 1992-01-31 | 1997-07-29 | University Of Montreal | Nucleozymes |
EP0642589A4 (en) * | 1992-05-11 | 1997-05-21 | Ribozyme Pharm Inc | METHOD AND REAGENT TO INHIBIT VIRAL REPLICATION. |
JPH07509133A (ja) * | 1992-07-17 | 1995-10-12 | リボザイム・ファーマシューティカルズ・インコーポレイテッド | 動物疾患の処置のための方法および剤 |
GB9225427D0 (en) * | 1992-12-04 | 1993-01-27 | Ribonetics Gmbh | Oligonucleotides with rna cleavage activity |
EP0748382B1 (en) * | 1993-09-02 | 2002-11-06 | Ribozyme Pharmaceuticals, Inc. | Non-nucleotide containing enzymatic nucleic acid |
US5672501A (en) * | 1994-12-23 | 1997-09-30 | Ribozyme Pharmaceuticals, Inc. | Base-modified enzymatic nucleic acid |
-
1994
- 1994-08-19 EP EP94925939A patent/EP0748382B1/en not_active Expired - Lifetime
- 1994-08-19 WO PCT/US1994/009342 patent/WO1995006731A2/en active IP Right Grant
- 1994-08-19 AT AT94925939T patent/ATE227342T1/de not_active IP Right Cessation
- 1994-08-19 PT PT94925939T patent/PT748382E/pt unknown
- 1994-08-19 CA CA002169645A patent/CA2169645A1/en not_active Abandoned
- 1994-08-19 DE DE69431669T patent/DE69431669T2/de not_active Expired - Fee Related
- 1994-08-19 JP JP7508146A patent/JPH09502092A/ja active Pending
- 1994-08-19 EP EP02009782A patent/EP1253199A1/en not_active Withdrawn
- 1994-08-19 ES ES94925939T patent/ES2186690T3/es not_active Expired - Lifetime
- 1994-08-19 EP EP05015038A patent/EP1602725A3/en not_active Withdrawn
- 1994-08-19 DK DK94925939T patent/DK0748382T3/da active
- 1994-12-23 US US08/363,253 patent/US5891683A/en not_active Expired - Lifetime
-
1998
- 1998-10-29 US US09/182,975 patent/US6117657A/en not_active Expired - Fee Related
-
2000
- 2000-07-31 US US09/628,959 patent/US6362323B1/en not_active Expired - Fee Related
-
2002
- 2002-01-08 US US10/041,614 patent/US6555668B2/en not_active Expired - Fee Related
-
2003
- 2003-03-17 US US10/390,206 patent/US6849726B2/en not_active Expired - Fee Related
-
2004
- 2004-04-16 JP JP2004121910A patent/JP3940407B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JPH09502092A (ja) | 1997-03-04 |
US6362323B1 (en) | 2002-03-26 |
EP1602725A3 (en) | 2006-03-29 |
US20030165969A1 (en) | 2003-09-04 |
JP2004215675A (ja) | 2004-08-05 |
US6117657A (en) | 2000-09-12 |
US6555668B2 (en) | 2003-04-29 |
EP1602725A2 (en) | 2005-12-07 |
US5891683A (en) | 1999-04-06 |
ATE227342T1 (de) | 2002-11-15 |
DK0748382T3 (da) | 2003-02-17 |
DE69431669T2 (de) | 2003-10-23 |
DE69431669D1 (de) | 2002-12-12 |
EP0748382B1 (en) | 2002-11-06 |
ES2186690T3 (es) | 2003-05-16 |
PT748382E (pt) | 2003-03-31 |
WO1995006731A3 (en) | 1995-07-06 |
EP0748382A1 (en) | 1996-12-18 |
EP1253199A1 (en) | 2002-10-30 |
WO1995006731A2 (en) | 1995-03-09 |
US6849726B2 (en) | 2005-02-01 |
US20020193579A1 (en) | 2002-12-19 |
CA2169645A1 (en) | 1995-03-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP3940407B2 (ja) | 非ヌクレオチドを含有する酵素性核酸 | |
EP0725788B1 (en) | 2'-amido and 2'-peptido modified oligonucleotides | |
US5610054A (en) | Enzymatic RNA molecule targeted against Hepatitis C virus | |
US6017756A (en) | Method and reagent for inhibiting hepatitis B virus replication | |
US6365374B1 (en) | 2′-deoxy-2′-alkylnucleotide containing nucleic acid | |
US5989906A (en) | Method and reagent for inhibiting P-glycoprotein (mdr-1-gene) | |
US5750390A (en) | Method and reagent for treatment of diseases caused by expression of the bcl-2 gene | |
US20030125291A1 (en) | Xylofuranosly-containing nucleoside phosphoramidites and polynucleotides | |
US5616490A (en) | Ribozymes targeted to TNF-α RNA | |
AU730934B2 (en) | Non-nucleotide containing enzymatic nucleic acid | |
WO1994029452A2 (en) | Enzymatic rna molecules and their application in the treatment of fibrosis and fibrous tissue disease | |
AU1457195A (en) | Non-nucleotide containing enzymatic nucleic acid | |
US6544755B1 (en) | Method and reagent for treatment of diseases by expression of the c-Myc gene | |
AU2022352668A1 (en) | Double stranded oligonucleotide compositions and methods relating thereto | |
US6492512B1 (en) | Method and reagent for treatment of lung cancer and other malignancies caused by the deregulation of L-MYC gene expression | |
JP2005516039A (ja) | 協同的オリゴヌクレオチド | |
MXPA96002770A (en) | Method and reagent to inhibit the replication of hepatiti virus |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20041227 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20051018 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20060117 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20060120 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060417 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20060516 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20060814 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20060817 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20061116 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20070306 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20070330 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110406 Year of fee payment: 4 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130406 Year of fee payment: 6 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140406 Year of fee payment: 7 |
|
LAPS | Cancellation because of no payment of annual fees |